KA Varady references with abstracts on PubMed, Dec. 10, 2013

1. Nutr J. 2013 Nov 12;12(1):146. [Epub ahead of print]

Alternate day fasting for weight loss in normal weight and overweight subjects: a
randomized controlled trial.

Varady KA, Bhutani S, Klempel MC, Kroeger CM, Trepanowski JF, Haus JM, Hoddy KK, 
Calvo Y.

BACKGROUND: Alternate day fasting (ADF; ad libitum "feed day", alternated with
25% energy intake "fast day"), is effective for weight loss and cardio-protection
in obese individuals. Whether these effects occur in normal weight and overweight
individuals remains unknown. This study examined the effect of ADF on body weight
and coronary heart disease risk in non-obese subjects.
METHODS: Thirty-two subjects (BMI 20--29.9 kg/m2) were randomized to either an
ADF group or a control group for 12 weeks.
RESULTS: Body weight decreased (P < 0.001) by 5.2 +/- 0.9 kg (6.5 +/- 1.0%) in
the ADF group, relative to the control group, by week 12. Fat mass was reduced (P
< 0.001) by 3.6 +/- 0.7 kg, and fat free mass did not change, versus controls.
Triacylglycerol concentrations decreased (20 +/- 8%, P < 0.05) and LDL particle
size increased (4 +/- 1 A, P < 0.01) in the ADF group relative to controls. CRP
decreased (13 +/- 17%, P < 0.05) in the ADF group relative to controls at week
12. Plasma adiponectin increased (6 +/- 10%, P < 0.01) while leptin decreased (40
+/- 7%, P < 0.05) in the ADF group versus controls by the end of the study. LDL
cholesterol, HDL cholesterol, homocysteine and resistin concentrations remained
unchanged after 12 weeks of treatment.
CONCLUSION: These findings suggest that ADF is effective for weight loss and
cardio-protection in normal weight and overweight adults, though further research
implementing larger sample sizes is required before solid conclusion can be
reached.

PMCID: PMC3833266
PMID: 24215592  [PubMed - as supplied by publisher]


2. J Int Soc Sports Nutr. 2013 Nov 1;10(1):50. [Epub ahead of print]

Effect of exercising while fasting on eating behaviors and food intake.

Bhutani S, Klempel MC, Kroeger CM, Aggour E, Calvo Y, Trepanowski JF, Hoddy KK,
Varady KA.

BACKGROUND: Alternate day fasting combined with exercise is effective for weight 
loss.
OBJECTIVE: The aim of this study was to examine the behavioral adaptations that
occur when ADF is combined with exercise, and to determine how these changes
affect weight loss.
DESIGN: Obese subjects (n = 64) were randomized to 1 of 4 groups: 1) combination 
(ADF + endurance exercise), 2) ADF, 3) exercise, or 4) control, for 12 weeks.
RESULTS: Body weight decreased (P < 0.05) in the combination group (6 +/- 4 kg), 
ADF (3 +/- 1 kg), exercise group (1 +/- 0 kg), with no change in the control
group (0 +/- 0 kg). When given the choice, subjects chose to exercise the same
amount (P = 0.790) on the fast days (48 +/- 2%) as feed days (52 +/- 2%). Percent
of exercise sessions performed on fast day mornings (20 +/- 6%) did not differ (P
= 0.453) from fast day afternoons (28 +/- 5%). Likeliness to cheat on the fast
day was not higher if the subject exercised in the afternoon (17 +/- 7%) versus
the morning (10 +/- 5%). Hunger decreased (P < 0.05) while satisfaction and
fullness increased (P < 0.05) post-treatment in the ADF group only. Restrained
eating increased (P < 0.05) and uncontrolled eating decreased (P < 0.05) in the
combination and ADF groups.
CONCLUSION: These findings suggest that endurance exercise is an excellent
adjunct therapy to ADF, as it leads to positive behavioral changes that may
contribute to long-term steady weight loss.

PMID: 24176020  [PubMed - as supplied by publisher]


3. Nutr Diabetes. 2013 May 27;3:e71. doi: 10.1038/nutd.2013.14.

Benefit of a low-fat over high-fat diet on vascular health during alternate day
fasting.

Klempel MC, Kroeger CM, Norkeviciute E, Goslawski M, Phillips SA, Varady KA.

Department of Kinesiology and Nutrition, University of Illinois at Chicago,
Chicago, IL, USA.

Background:Alternate day fasting (ADF) with a low-fat (LF) diet improves brachial
artery flow-mediated dilation (FMD). Whether these beneficial effects can be
reproduced with a high-fat (HF) diet remains unclear.Objective:This study
compared the effects of ADF-HF to ADF-LF regimens on FMD. The role that
adipokines have in mediating this effect was also investigated.Methods:Thirty-two
obese subjects were randomized to an ADF-HF (45% fat) or ADF-LF diet (25% fat),
consisting of two phases: (1) a 2-week baseline weight maintenance period and (2)
an 8-week ADF weight loss period. Food was provided throughout the
study.Results:Body weight was reduced (P<0.0001) in the ADF-HF (4.4±1.0 kg) and
ADF-LF group (3.7±0.7 kg). FMD decreased (P<0.05) by ADF-HF relative to baseline 
(7±1 to 5±2%) and increased (P<0.05) by ADF-LF (5±1 to 7±2%). Blood pressure
remained unchanged in both groups. Adiponectin increased (P<0.05) in the ADF-HF
(43±7%) and ADF-LF group (51±7%). Leptin and resistin decreased (P<0.05) in the
ADF-HF (32±5%; 23±5%) and ADF-LF group (30±3%; 27±4%). Increases in adiponectin
were associated with augmented FMD in the ADF-LF group only (r=0.34,
P=0.03).Conclusion:Thus, improvements in FMD with ADF may only occur with LF
diets and not with HF diets, and adipokines may not have a significant role in
mediating this effect.

PMCID: PMC3671747
PMID: 23712283  [PubMed]


4. Eur J Clin Nutr. 2013 Jul;67(7):783-5. doi: 10.1038/ejcn.2013.83. Epub 2013 Apr
24.

Alternate day fasting increases LDL particle size independently of dietary fat
content in obese humans.

Klempel MC, Kroeger CM, Varady KA.

Department of Kinesiology and Nutrition, University of Illinois, Chicago, IL,
USA.

Alternate day fasting (ADF) with a low-fat (LF) diet increases low-density
lipoprotein (LDL) particle size. Whether these beneficial effects can be
reproduced by a high-fat (HF) ADF diet is unclear. This study compared an ADF-HF 
to an ADF-LF diet on plasma lipids, LDL size and high-density lipoprotein (HDL)
size. Thirty-five obese subjects were randomized to an ADF-HF or ADF-LF diet for 
10 weeks. Body weight decreased (P<0.0001) by 4.3±1.0 kg (4.8±1.1%) and
3.7±0.7 kg (4.2±0.8%) in the ADF-HF and ADF-LF group, respectively. LDL
cholesterol was reduced (P<0.0001) by 19±8 mg/dl (18±5%) by ADF-HF and 28±7 mg/dl
(25±3%) by ADF-LF. LDL particle size increased (P<0.005) by 3±1 Å in both groups.
The proportion of small LDL particles decreased (P<0.005) by 8±2% and 11±3% in
the ADF-HF and ADF-LF groups, respectively. HDL cholesterol and HDL size remained
unchanged. Thus, our results suggest that the ADF-HF diet is equally as effective
as the ADF-LF diet in improving LDL particle size and distribution.

PMID: 23612508  [PubMed - in process]


5. Obesity (Silver Spring). 2013 Jul;21(7):1370-9. doi: 10.1002/oby.20353. Epub 2013
May 29.

Alternate day fasting and endurance exercise combine to reduce body weight and
favorably alter plasma lipids in obese humans.

Bhutani S, Klempel MC, Kroeger CM, Trepanowski JF, Varady KA.

Department of Kinesiology and Nutrition, University of Illinois at Chicago,
Chicago, IL, USA. sbhuta2@uic.edu

OBJECTIVE: This study examined whether the combination of alternate day fasting
(ADF) plus exercise produces superior changes in body composition and plasma
lipid levels when compared to each intervention alone.
DESIGN AND METHODS: Obese subjects (n = 64) were randomized to 1 of 4 groups for 
12 weeks: 1) combination (ADF plus endurance exercise), 2) ADF, 3) exercise, or
4) control.
RESULTS: Body weight was reduced (P < 0.05) by 6 ± 4 kg, 3 ± 1 kg, and 1 ± 0 kg
in the combination, ADF, and exercise groups, respectively. Fat mass and waist
circumference decreased (P < 0.001), while lean mass was retained in the
combination group. Low-density lipoprotein (LDL) cholesterol decreased (12 ± 5%, 
P < 0.05) and high-density lipoprotein (HDL) cholesterol increased (18 ± 9%, P < 
0.05) in the combination group only. LDL particle size increased (P < 0.001) by 4
± 1 Å and 5 ± 1 Å in the combination and ADF groups, respectively. The proportion
of small HDL particles decreased (P < 0.01) in the combination group only.
CONCLUSIONS: These findings suggest that the combination produces superior
changes in body weight, body composition, and lipid indicators of heart disease
risk, when compared to individual treatments.

Copyright © 2013 The Obesity Society.

PMID: 23408502  [PubMed - in process]


6. Nutr J. 2012 Nov 21;11:98. doi: 10.1186/1475-2891-11-98.

Intermittent fasting combined with calorie restriction is effective for weight
loss and cardio-protection in obese women.

Klempel MC, Kroeger CM, Bhutani S, Trepanowski JF, Varady KA.

Department of Kinesiology and Nutrition, University of Illinois at Chicago, 1919 
West Taylor Street, Room 506F, Chicago, IL 60612, USA.

BACKGROUND: Intermittent fasting (IF; severe restriction 1 d/week) facilitates
weight loss and improves coronary heart disease (CHD) risk indicators. The degree
to which weight loss can be enhanced if IF is combined with calorie restriction
(CR) and liquid meals, remains unknown.
OBJECTIVE: This study examined the effects of IF plus CR (with or without a
liquid diet) on body weight, body composition, and CHD risk.
METHODS: Obese women (n = 54) were randomized to either the IFCR-liquid (IFCR-L) 
or IFCR-food based (IFCR-F) diet. The trial had two phases: 1) 2-week weight
maintenance period, and 2) 8-week weight loss period.
RESULTS: Body weight decreased more (P = 0.04) in the IFCR-L group (3.9 ± 1.4 kg)
versus the IFCR-F group (2.5 ± 0.6 kg). Fat mass decreased similarly (P < 0.0001)
in the IFCR-L and IFCR-F groups (2.8 ± 1.2 kg and 1.9 ± 0.7 kg, respectively).
Visceral fat was reduced (P < 0.001) by IFCR-L (0.7 ± 0.5 kg) and IFCR-F (0.3 ±
0.5 kg) diets. Reductions in total and LDL cholesterol levels were greater (P =
0.04) in the IFCR-L (19 ± 10%; 20 ± 9%, respectively) versus the IFCR-F group (8 
± 3%; 7 ± 4%, respectively). LDL peak particle size increased (P < 0.01), while
heart rate, glucose, insulin, and homocysteine decreased (P < 0.05), in the
IFCR-L group only.
CONCLUSION: These findings suggest that IF combined with CR and liquid meals is
an effective strategy to help obese women lose weight and lower CHD risk.

PMCID: PMC3511220
PMID: 23171320  [PubMed - indexed for MEDLINE]


7. Nutr Metab (Lond). 2012 Oct 31;9(1):98. doi: 10.1186/1743-7075-9-98.

Improvement in coronary heart disease risk factors during an intermittent
fasting/calorie restriction regimen: Relationship to adipokine modulations.

Kroeger CM, Klempel MC, Bhutani S, Trepanowski JF, Tangney CC, Varady KA.

Department of Kinesiology and Nutrition, University of Illinois at Chicago,
Chicago, IL, USA. varady@uic.edu.

BACKGROUND: The ability of an intermittent fasting (IF)-calorie restriction (CR) 
regimen (with or without liquid meals) to modulate adipokines in a way that is
protective against coronary heart disease (CHD) has yet to be tested.
OBJECTIVE: Accordingly, we examined the effects of an IFCR diet on adipokine
profile, body composition, and markers of CHD risk in obese women.
METHODS: Subjects (n = 54) were randomized to either the IFCR-liquid (IFCR-L) or 
IFCR-food based (IFCR-F) diet for 10 weeks.
RESULTS: Greater decreases in body weight and waist circumference were noted in
the IFCR-L group (4 ± 1 kg; 6 ± 1 cm) versus the IFCR-F group (3 ± 1 kg; 4 ± 1
cm). Similar reductions (P < 0.0001) in fat mass were demonstrated in the IFCR-L 
(3 ± 1 kg) and IFCR-F group (2 ± 1 kg). Reductions in total and LDL cholesterol
levels were greater (P = 0.04) in the IFCR-L (19 ± 10%; 20 ± 9%, respectively)
versus the IFCR-F group (8 ± 3%; 7 ± 4%, respectively). LDL peak particle size
increased (P < 0.01) in the IFCR-L group only. The proportion of small LDL
particles decreased (P < 0.01) in both groups. Adipokines, such as leptin,
interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and insulin-like
growth factor-1 (IGF-1) decreased (P < 0.05), in the IFCR-L group only.
CONCLUSION: These findings suggest that IFCR with a liquid diet favorably
modulates visceral fat and adipokines in a way that may confer protection against
CHD.

PMCID: PMC3514278
PMID: 23113919  [PubMed]


8. Metabolism. 2013 Jan;62(1):137-43. doi: 10.1016/j.metabol.2012.07.002. Epub 2012 
Aug 11.

Alternate day fasting (ADF) with a high-fat diet produces similar weight loss and
cardio-protection as ADF with a low-fat diet.

Klempel MC, Kroeger CM, Varady KA.

Department of Kinesiology and Nutrition, University of Illinois at Chicago, 1919 
West Taylor Street, Room 506F, Chicago, IL 60612, USA.

Alternate day fasting (ADF) with a low-fat (LF) diet is effective for weight loss
and cardio-protection. However, the applicability of these findings is
questionable as the majority of Americans consume a high-fat (HF) diet.OBJECTIVE:
The goal of this study was to determine if these beneficial changes in body
weight and coronary heart disease (CHD) risk can be reproduced if an HF
background diet is used in place of an LF diet during ADF.
METHODS: Thirty-two obese subjects were randomized to an ADF-HF (45% fat) or
ADF-LF diet (25% fat), which consisted of two phases: 1) a 2-week baseline weight
maintenance period, and 2) an 8-week ADF weight loss period. All food was
provided during the study.
RESULTS: Body weight was reduced (P<0.0001) by ADF-HF (4.8%±1.1%) and by ADF-LF
(4.2%±0.8%). Fat mass decreased (P<0.0001) by ADF-HF (5.4±1.5 kg) and ADF-LF
(4.2±0.6 kg). Fat free mass remained unchanged. Waist circumference decreased
(P<0.001) by ADF-HF (7.2±1.5 cm) and ADF-LF (7.3±0.9 cm). LDL cholesterol and
triacylglycerol concentrations were reduced (P<0.001) by both interventions
(ADF-HF: 18.3%±4.6%, 13.7%±4.8%; and ADF-LF: 24.8%±2.6%, 14.3%±4.4%). HDL
cholesterol, blood pressure, and heart rate remained unchanged. There were no
between-group differences for any parameter.
CONCLUSION: These findings suggest that an ADF-HF diet is equally as effective as
an ADF-LF diet in helping obese subjects lose weight and improve CHD risk
factors.

Copyright © 2013 Elsevier Inc. All rights reserved.

PMID: 22889512  [PubMed - indexed for MEDLINE]


9. Lipids. 2011 Dec;46(12):1163-7. doi: 10.1007/s11745-011-3611-8. Epub 2011 Sep 21.

Lipoprint adequately estimates LDL size distribution, but not absolute size,
versus polyacrylamide gradient gel electrophoresis.

Varady KA, Lamarche B.

Department of Kinesiology and Nutrition, University of Illinois at Chicago, USA. 
varady@uic.edu

Recently, a new cost-effective and less labor-intensive technique termed the
"lipoprint LDL system" was developed to measure LDL particle size. However, the
agreement between lipoprint and previously validated techniques, such as
polyacrylamide gradient gel electrophoresis (PGGE), has never been tested.
Therefore, we measured LDL size by lipoprint and PGGE in 16 obese subjects at 4
different time points. Lipoprint significantly overestimated (P = 0.003)
integrated LDL particle size by 1.1 ± 3.0 Å when compared to PGGE. As for
distribution, there was good agreement between methods for the estimation of
large, medium, and small particles (mean difference between the methods was <3%
for each parameter). Correlational analysis also revealed good relationships
between methods for the proportion of large (r = 0.81, P < 0.0001), medium
(r = 0.67, P < 0.0001), and small (r = 0.73, P < 0.0001) particles. In sum,
although there is good agreement between lipoprint and PGGE for the determination
of LDL size distribution, absolute LDL size values may differ between the two
methods.

PMID: 21935654  [PubMed - indexed for MEDLINE]


10. Lipids Health Dis. 2011 Jul 18;10:119. doi: 10.1186/1476-511X-10-119.

Comparison of effects of diet versus exercise weight loss regimens on LDL and HDL
particle size in obese adults.

Varady KA, Bhutani S, Klempel MC, Kroeger CM.

Department of Kinesiology and Nutrition, University of Illinois at Chicago,
Chicago, IL, USA. varady@uic.edu

BACKGROUND: Obesity is associated with an atherogenic lipid profile characterized
by a predominance of small LDL and HDL particles. Weight loss, by dietary
restriction or exercise, increases LDL particle size. Whether these interventions
can augment HDL size in conjunction with LDL size remains unknown.
OBJECTIVE: This study compared the effects of alternate day fasting (ADF),
calorie restriction (CR), and endurance exercise on LDL and HDL particle size in 
overweight and obese subjects.
METHODS: In a 12-week parallel-arm trial, adult subjects (n = 60) were randomized
to 1 of 4 groups: 1) ADF (75% energy restriction for 24-h alternated with ad
libitum feeding for 24-h), 2) CR (25% energy restriction every day), 3) exercise 
(moderate intensity training 3 x/week), or 4) control.
RESULTS: Body weight was reduced (P < 0.001) by ADF, CR, and exercise (5.2 ±
1.1%, 5.0 ± 1.4%, 5.1 ± 0.9%, respectively). Plasma LDL cholesterol decreased (P 
< 0.05) with ADF (10 ± 4%) and CR (8 ± 4%), whereas HDL cholesterol increased (P 
< 0.05) with exercise (16 ± 5%). Integrated LDL particle size was augmented (P = 
0.01) by ADF and CR. The proportion of small LDL particles decreased (P = 0.04)
with ADF only, and the proportion of large HDL particles increased (P = 0.03)
with exercise only.
CONCLUSION: These results indicate that dietary restriction increases LDL
particle size, while endurance training augments HDL particle size, with minimal 
weight loss. None of these interventions concomitantly increased both LDL and HDL
particle size, however.

PMCID: PMC3150311
PMID: 21767400  [PubMed - indexed for MEDLINE]


11. Obes Rev. 2011 Jul;12(7):e593-601. doi: 10.1111/j.1467-789X.2011.00873.x. Epub
2011 Mar 17.

Intermittent versus daily calorie restriction: which diet regimen is more
effective for weight loss?

Varady KA.

Department of Kinesiology and Nutrition, University of Illinois at Chicago,
Chicago, IL 60612, USA. varady@uic.edu

Dietary restriction is an effective strategy for weight loss in obese
individuals. The most common form of dietary restriction implemented is daily
calorie restriction (CR), which involves reducing energy by 15-60% of usual
caloric intake every day. Another form of dietary restriction employed is
intermittent CR, which involves 24 h of ad libitum food consumption alternated
with 24 h of complete or partial food restriction. Although both diets are
effective for weight loss, it remains unknown whether one of these interventions 
produces superior changes in body weight and body composition when compared to
the other. Accordingly, this review examines the effects of daily CR versus
intermittent CR on weight loss, fat mass loss and lean mass retention in
overweight and obese adults. Results reveal similar weight loss and fat mass loss
with 3 to 12 weeks' intermittent CR (4-8%, 11-16%, respectively) and daily CR
(5-8%, 10-20%, respectively). In contrast, less fat free mass was lost in
response to intermittent CR versus daily CR. These findings suggest that these
diets are equally as effective in decreasing body weight and fat mass, although
intermittent CR may be more effective for the retention of lean mass.

© 2011 The Author. obesity reviews © 2011 International Association for the Study
of Obesity.

PMID: 21410865  [PubMed - indexed for MEDLINE]


12. Nutr Rev. 2011 Mar;69(3):145-54. doi: 10.1111/j.1753-4887.2011.00373.x. Epub 2011
Feb 14.

Reliability of leptin, but not adiponectin, as a biomarker for diet-induced
weight loss in humans.

Klempel MC, Varady KA.

Department of Kinesiology and Nutrition, University of Illinois at Chicago,
Chicago, Illinois 60612, USA. varady@uic.edu

Calorie restriction (CR)-induced weight loss has been shown to lower the risk of 
chronic disease in obese individuals. Although the mechanisms that link weight
loss to disease risk reduction remain unclear, evidence suggests adipokines may
play a role. What has yet to be determined, however, is the dose-response effect 
of body weight loss and visceral fat mass loss on adipokines. Accordingly, this
review examines how varying degrees of CR-induced weight loss (i.e., >10%, 5-10%,
and <5% from baseline) impact plasma levels and expression of adiponectin,
leptin, resistin, interleukin 6 (IL-6), interleukin 8 (IL-8), monocyte
chemotactic protein 1 (MCP-1), and retinol-binding protein 4 (RBP-4). The
dose-response relationship between visceral fat mass loss and adipokine profile
improvement will also be explored. Results from this review demonstrate that even
mild weight loss induced by CR may have beneficial effects on leptin levels, but 
it has no clear impact on adiponectin, resistin, IL-6, IL-8, MCP-1, or RBP-4
concentrations.

© 2011 International Life Sciences Institute.

PMID: 21348878  [PubMed - indexed for MEDLINE]


13. Nutr J. 2011 Jan 20;10:8. doi: 10.1186/1475-2891-10-8.

Improvements in vascular health by a low-fat diet, but not a high-fat diet, are
mediated by changes in adipocyte biology.

Varady KA, Bhutani S, Klempel MC, Phillips SA.

Department of Kinesiology and Nutrition, University of Illinois, Chicago,
Chicago, IL, USA. varady@uic.edu

BACKGROUND: Low-fat (LF) and high-fat (HF) weight loss diets improve brachial
artery flow-mediated dilation (FMD) in obese individuals, although results are
conflicting. Moreover, the role that adipose tissue plays in mediating these
diet-related effects are unknown.
OBJECTIVE: This study examined how modulations in FMD by HF and LF diets relate
to changes in adipocyte parameters.
DESIGN: Obese subjects (n = 17) were randomized to a HF diet (60% kcal as fat) or
a LF diet (25% kcal as fat) for 6 weeks. Both groups were restricted by 25% of
energy needs.
RESULTS: Body weight decreased (P <0.05) in both groups (HF: -6.6 ± 0.5 kg, LF:
-4.7 ± 0.6 kg). Fat mass and waist circumference were reduced (P <0.05) in the LF
group only (-4.4 ± 0.3 kg; -3.6 ± 0.8 cm, respectively). FMD improved (P <0.05)
in the LF group (7.4 ± 0.8% to 9.8 ± 0.8; 32% increase) and was impaired in the
HF group (8.5 ± 0.6% to 6.9 ± 0.7; 19% reduction). Increases in plasma
adiponectin (P <0.05, 16 ± 5%), and decreases in resistin (P <0.05, -26 ± 11%),
were shown by the LF diet only. Greater decreases in leptin were observed with LF
(-48 ± 9%) versus HF (-28 ± 12%) (P <0.05, diet × time). Increased FMD by the LF 
diet was associated with increased adiponectin, and decreased fat mass, waist
circumference, leptin, and resistin.
CONCLUSION: Beneficial modulations in vascular health by LF diets may be mediated
by improvements in adipocyte parameters.

PMCID: PMC3032663
PMID: 21251283  [PubMed - indexed for MEDLINE]


14. Br J Nutr. 2011 Feb;105(4):580-3. doi: 10.1017/S0007114510003788. Epub 2010 Sep
30.

Improvements in LDL particle size and distribution by short-term alternate day
modified fasting in obese adults.

Varady KA, Bhutani S, Klempel MC, Lamarche B.

Department of Kinesiology and Nutrition, University of Illinois at Chicago, 1919 
West Taylor Street, Room 506F, Chicago, IL 60612, USA. varady@uic.edu

Alternate day modified fasting (ADMF) beneficially modulates several indicators
of CHD risk, but its effects on LDL particle size have never been tested.
Accordingly, we examined the effects of ADMF on LDL particle size and
distribution in obese adults. Sixteen obese subjects participated in a 10-week
trial with three consecutive phases: (1) 2-week control phase; (2) 4-week ADMF
controlled feeding phase; (3) 4-week ADMF self-selected feeding phase. After 8
weeks of diet, body weight and waist circumference were reduced (P < 0·05) by 5·6
(sem 0·9) kg and 4·0 (sem 0·9) cm, respectively. LDL-cholesterol and TAG
concentrations decreased (P < 0·05) by 25 (sem 10) % and 32 (sem 6) %,
respectively. Peak LDL particle size increased (P < 0·05) from 266 (sem 1) to 268
(sem 1) Å. Additionally, the proportion of small LDL particles decreased
(P < 0·05) from 13 (sem 2) % to 9 (sem 3) %, while the proportion of large LDL
particles increased (P < 0·05) from 68 (sem 4) % to 76 (sem 4) % post-treatment. 
These findings suggest that ADMF is an effective diet strategy for increasing LDL
particle size and decreasing the proportion of small, dense LDL particles in
obese adults.

PMID: 20880415  [PubMed - indexed for MEDLINE]


15. Nutr J. 2010 Sep 3;9:35. doi: 10.1186/1475-2891-9-35.

Dietary and physical activity adaptations to alternate day modified fasting:
implications for optimal weight loss.

Klempel MC, Bhutani S, Fitzgibbon M, Freels S, Varady KA.

Department of Kinesiology and Nutrition, University of Illinois at Chicago, IL,
USA.

BACKGROUND: Alternate day modified fasting (ADMF) is an effective strategy for
weight loss in obese adults.
OBJECTIVE: The objective of this study was to examine the dietary and physical
activity adaptations that occur during short-term ADMF, and to determine how
these modulations affect rate of weight loss.
METHODS: Sixteen obese subjects (12 women/4 men) completed a 10-week trial
consisting of 3 phases: 1) 2-week control phase, 2) 4-week ADMF controlled
feeding phase, and 3) 4-week ADMF self-selected feeding phase.
RESULTS: Body weight decreased (P < 0.001) by 5.6 ± 1.0 kg post-treatment. Energy
intake on the fast day was 26 ± 3% of baseline needs (501 ± 28 kcal/d). No
hyperphagic response occurred on the feed day (95 ± 6% of baseline needs
consumed, 1801 ± 226 kcal/d). Daily energy restriction (37 ± 7%) was correlated
to rate of weight loss (r = 0.42, P = 0.01). Dietary fat intake decreased (36% to
33% of kcal, P < 0.05) with dietary counseling, and was related to rate of weight
loss (r = 0.38, P = 0.03). Hunger on the fast day decreased (P < 0.05) by week 2,
and remained low. Habitual physical activity was maintained throughout the study 
(fast day: 6416 ± 851 steps/d; feed day: 6569 ± 910 steps/d).
CONCLUSION: These findings indicate that obese subjects quickly adapt to ADMF,
and that changes in energy/macronutrient intake, hunger, and maintenance of
physical activity play a role in influencing rate of weight loss by ADMF.

PMCID: PMC2941474
PMID: 20815899  [PubMed - indexed for MEDLINE]


16. Obesity (Silver Spring). 2010 Nov;18(11):2152-9. doi: 10.1038/oby.2010.54. Epub
2010 Mar 18.

Improvements in coronary heart disease risk indicators by alternate-day fasting
involve adipose tissue modulations.

Bhutani S, Klempel MC, Berger RA, Varady KA.

Department of Kinesiology and Nutrition, University of Illinois at Chicago,
Chicago, Illinois, USA.

The ability of alternate-day fasting (ADF) to modulate adipocyte parameters in a 
way that is protective against coronary heart disease (CHD) has yet to be tested.
Accordingly, we examined the effects of ADF on adipokine profile, body
composition, and CHD risk indicators in obese adults. Sixteen obese subjects (12 
women/4 men) participated in a 10-week trial with three consecutive dietary
intervention phases: (i) 2-week baseline control phase, (ii) 4-week ADF
controlled feeding phase, and (iii) 4-week ADF self-selected feeding phase. After
8 weeks of treatment, body weight and waist circumference were reduced (P < 0.05)
by 5.7 ± 0.9 kg, and 4.0 ± 0.9 cm, respectively. Fat mass decreased (P < 0.05) by
5.4 ± 0.8 kg, whereas fat-free mass did not change. Plasma adiponectin was
augmented (P < 0.05) by 30% from baseline. Leptin and resistin concentrations
were reduced (P < 0.05) by 21 and 23%, respectively, post treatment. Low-density 
lipoprotein cholesterol (LDL-C) and triacylglycerol concentrations were 25% and
32% lower (P < 0.05), respectively, after 8 weeks of ADF. High-density
lipoprotein cholesterol (HDL-C), C-reactive protein, and homocysteine
concentrations did not change. Decreases in LDL-C were related to increased
adiponectin (r = -0.61, P = 0.01) and reduced waist circumference (r = 0.39, P = 
0.04). Lower triacylglycerol concentrations were associated with augmented
adiponectin (r = -0.39, P = 0.04) and reduced leptin concentrations (r = 0.45, P 
= 0.03) post-treatment. These findings suggest that adipose tissue parameters may
play an important role in mediating the cardioprotective effects of ADF in obese 
humans.

PMID: 20300080  [PubMed - indexed for MEDLINE]


17. J Pharmacol Exp Ther. 2010 Apr;333(1):281-9. doi: 10.1124/jpet.109.162487. Epub
2010 Jan 11.

Differential in vivo effects on target pathways of a novel arylpyrazole
glucocorticoid receptor modulator compared with prednisolone.

Roohk DJ, Varady KA, Turner SM, Emson CL, Gelling RW, Shankaran M, Lindwall G,
Shipp LE, Scanlan TS, Wang JC, Hellerstein MK.

Department of Nutritional Sciences and Toxicology, 309 Morgan Hall, University of
California, Berkeley, CA 94720-3104, USA. djroohk@berkeley.edu

Glucocorticoids are widely prescribed to treat autoimmune and inflammatory
diseases. Although they are extremely potent, their utility in clinical practice 
is limited by a variety of adverse side effects. Development of compounds that
retain the potent immunomodulating and anti-inflammatory properties of classic
glucocorticoids while exhibiting reduced adverse actions is therefore a priority.
Using heavy water labeling and mass spectrometry to measure fluxes through
multiple glucocorticoid-responsive, disease-relevant target pathways in vivo in
mice, we compared the effects of a classic glucocorticoid receptor (GR) ligand,
prednisolone, with those of a novel arylpyrazole-based compound, L5
{[1-(4-fluorophenyl)-4a-methyl-5,6,7,8-tetrahydro-4H-benzo[f]indazol-5-yl]-[4-(tr
ifluoromethyl)phenyl]methanol}. We show for the first time that L5 exhibits
clearly selective actions on disease-relevant pathways compared with
prednisolone. Prednisolone reduced bone collagen synthesis, skin collagen
synthesis, muscle protein synthesis, and splenic lymphocyte counts,
proliferation, and cell death, whereas L5 had none of those actions. In contrast,
L5 was a more rapid and potent inhibitor of hippocampal neurogenesis than
prednisolone, and L5 and prednisolone induced insulin resistance equally.
Administration of prednisolone or L5 increased expression comparably for one
GR-regulated gene involved in protein degradation in skeletal muscle (Murf1) and 
one GR-regulated gluconeogenic gene in liver (PEPCK). In summary, L5 dissociates 
the pleiotropic effects of the GR ligand prednisolone in intact animals in ways
that neither gene expression nor cell-based models were able to fully capture or 
predict. Because multiple actions can be measured concurrently in a single
animal, this method is a powerful systems approach for characterizing and
differentiating the effects of ligands that bind nuclear receptors.

PMID: 20065017  [PubMed - indexed for MEDLINE]


18. Med Sci Sports Exerc. 2010 Mar;42(3):456-62. doi: 10.1249/MSS.0b013e3181ba6dd3.

Adipokine responses to acute resistance exercise in trained and untrained men.

Varady KA, Bhutani S, Church EC, Phillips SA.

Department of Kinesiology and Nutrition, University of Illinois at Chicago,
Chicago, IL 60612, USA. varady@uic.edu

INTRODUCTION: Adipose tissue-derived hormones act as key mediators that may link 
active lifestyles to improved cardiovascular function. This study tested the
hypothesis that a single weight training session would beneficially modulate
adipokine profile in a way that would exert protection against endothelial
dysfunction, in trained but not sedentary subjects.
METHODS: Male subjects (n = 43) were categorized into four separate groups based 
on exercise history: 1) sedentary, 2) weight trainers, 3) runners, or 4) weight
trainer + runners. All subjects underwent a single progressive leg press weight
training session (low weight for two sets of 8-12 repetitions each and then
near-maximal exertion for three sets of 8-12 repetitions each).
RESULTS: There were no differences between groups for age, body weight, BMI,
waist circumference, or percent body fat. Adiponectin increased (P < 0.05) by 30%
and 37%, whereas resistin decreased (P < 0.05) by 35% and 34% in the weight
trainers and weight trainer + runners, respectively, after training.
Flow-mediated dilation (FMD) was impaired (P < 0.05) in sedentary subjects (-1.1 
+/- 0.3%) but not in the athletic groups (1.7 +/- 0.4%). Improvements in FMD were
associated with increased adiponectin (r = 0.61, P = 0.01), and decreased
resistin (r = -0.56, P = 0.01) in weight trainers only. Leptin was not altered by
acute resistance training in any group. There were no differences after training 
for total, LDL, HDL cholesterol, triglycerides, C-reactive protein levels, and
systolic or diastolic blood pressure. Increased adiponectin was related to higher
levels of HDL cholesterol after intervention (r = 0.71, P = 0.001).
CONCLUSIONS: These findings suggest that habitual resistance training may
modulate adipokine profiles in a way that is protective against endothelial
dysfunction.

PMID: 19952805  [PubMed - indexed for MEDLINE]


19. Am J Clin Nutr. 2009 Nov;90(5):1138-43. doi: 10.3945/ajcn.2009.28380. Epub 2009
Sep 30.

Short-term modified alternate-day fasting: a novel dietary strategy for weight
loss and cardioprotection in obese adults.

Varady KA, Bhutani S, Church EC, Klempel MC.

Department of Kinesiology and Nutrition, University of Illinois at Chicago,
Chicago, IL 60612, USA. varady@uic.edu

BACKGROUND: The ability of modified alternate-day fasting (ADF; ie, consuming 25%
of energy needs on the fast day and ad libitum food intake on the following day) 
to facilitate weight loss and lower vascular disease risk in obese individuals
remains unknown.
OBJECTIVE: This study examined the effects of ADF that is administered under
controlled compared with self-implemented conditions on body weight and coronary 
artery disease (CAD) risk indicators in obese adults.
DESIGN: Sixteen obese subjects (12 women, 4 men) completed a 10-wk trial, which
consisted of 3 phases: 1) a 2-wk control phase, 2) a 4-wk weight loss/ADF
controlled food intake phase, and 3) a 4-wk weight loss/ADF self-selected food
intake phase.
RESULTS: Dietary adherence remained high throughout the controlled food intake
phase (days adherent: 86%) and the self-selected food intake phase (days
adherent: 89%). The rate of weight loss remained constant during controlled food 
intake (0.67 +/- 0.1 kg/wk) and self-selected food intake phases (0.68 +/- 0.1
kg/wk). Body weight decreased (P < 0.001) by 5.6 +/- 1.0 kg (5.8 +/- 1.1%) after 
8 wk of diet. Percentage body fat decreased (P < 0.01) from 45 +/- 2% to 42 +/-
2%. Total cholesterol, LDL cholesterol, and triacylglycerol concentrations
decreased (P < 0.01) by 21 +/- 4%, 25 +/- 10%, and 32 +/- 6%, respectively, after
8 wk of ADF, whereas HDL cholesterol remained unchanged. Systolic blood pressure 
decreased (P < 0.05) from 124 +/- 5 to 116 +/- 3 mm Hg.
CONCLUSION: These findings suggest that ADF is a viable diet option to help obese
individuals lose weight and decrease CAD risk. This trial was registered at
clinicaltrials.gov as UIC-004-2009.

PMID: 19793855  [PubMed - indexed for MEDLINE]


20. Nutr Rev. 2009 Oct;67(10):591-8. doi: 10.1111/j.1753-4887.2009.00231.x.

Nibbling versus feasting: which meal pattern is better for heart disease
prevention?

Bhutani S, Varady KA.

Department of Kinesiology, University of Illinois at Chicago, Chicago, Illinois
60612, USA.

Dietary interventions that limit saturated fat, cholesterol, and energy are
generally implemented as the first line of therapy to reduce the risk of coronary
heart disease (CHD). Another form of diet therapy that may be effective in
protecting against CHD is altering meal frequency without limiting energy.
Meal-frequency regimens are classified into two major forms: 1) feasting, i.e.,
consuming all energy needs in one meal/day, and 2) nibbling, i.e., consuming all 
energy needs in three, six, nine, 12, or 17 regimented meals/day. Whether one
meal pattern, feasting or nibbling, is more effective at improving indicators of 
CHD risk than the other, remains unresolved. Moreover, whether a dose-dependent
relationship exists between biomarker improvement and the number of meals
consumed per day also remains unknown. The objective of the present review was to
determine which meal pattern, nibbling or feasting, is more effective at
improving key indicators of CHD risk in normal-weight and obese, non-diabetic
individuals.

PMID: 19785690  [PubMed - indexed for MEDLINE]


21. Metabolism. 2009 Aug;58(8):1096-101. doi: 10.1016/j.metabol.2009.04.010. Epub
2009 Jun 18.

Degree of weight loss required to improve adipokine concentrations and decrease
fat cell size in severely obese women.

Varady KA, Tussing L, Bhutani S, Braunschweig CL.

Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL 60612, 
USA. varady@uic.edu

Adipose tissue physiology plays an important role in mediating disease risk.
Weight loss in obese individuals improves indicators of adipocyte physiology.
However, the minimum degree of weight loss required to elicit improvements
remains unknown. The objective of the present study was to determine the minimum 
weight loss required to improve adipokine profile and decrease fat cell size in
severely obese women. Thirteen severely obese women (body mass index, 50 +/- 3
kg/m(2); age, 35 +/- 1 years) consumed a low-calorie diet for 3 weeks with the
goal of losing 5% of their initial weight. Subjects were divided into 2 weight
loss groups posttreatment: less than 5% weight loss and 5% to 10% weight loss.
Body weight was reduced (P < .05) in both groups (-1.4 +/- 1.0 and -6.8 +/- 0.6
kg, respectively). Adiponectin concentrations increased (P < .05) by 20% in the
5% to 10% weight loss group only. Likewise, leptin and resistin decreased (P <
.05) by 37% and 27%, respectively, in the group that lost more weight. Visceral
and subcutaneous fat cell size was 41% and 37% smaller (P < .01), respectively,
in the 5% to 10% weight loss group. Smaller visceral adipocyte size was related
to lower insulin (r = 0.82, P = .01) and glucose (r = 0.58, P = .04)
concentrations posttreatment. These findings suggest that a minimum weight loss
of 5% is required to improve adipokine profile and decrease fat cell size in
severely obese women. These changes in adipocyte physiology may be linked to
reductions in metabolic disease risk in this population.

PMID: 19477470  [PubMed - indexed for MEDLINE]


22. Metabolism. 2009 Jun;58(6):803-11. doi: 10.1016/j.metabol.2009.01.018.

Modified alternate-day fasting and cardioprotection: relation to adipose tissue
dynamics and dietary fat intake.

Varady KA, Hudak CS, Hellerstein MK.

Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL 60612, 
USA. kvarady@gmail.com

The relation between alternate-day fasting (ADF) and cardioprotection remains
uncertain. In the present study, we examined the ability of modified ADF, with a 
low-fat (LF) vs high-fat (HF) background diet, to modulate adipose tissue
physiology in a way that may protect against coronary heart disease. In a 4-week 
study, male C57BL/6 mice were randomized to 1 of 3 groups: (1) ADF-85%-LF (85%
energy restriction on fast day, ad libitum fed on feed day, on an LF diet), (2)
ADF-85%-HF (same protocol but HF diet), and (3) control (ad libitum fed).
Throughout the study, body weight did not differ between ADF and control animals.
Proportion of subcutaneous fat increased (P < .01), whereas the proportion of
visceral fat decreased (P < .01), in both ADF groups. Triglyceride (TG) synthesis
was augmented (P < .05) in subcutaneous fat, but remained unchanged in visceral
fat. Adiponectin concentrations were elevated (P < .05), whereas leptin and
resistin levels decreased (P < .05). Aortic vascular smooth muscle cell
proliferation was reduced (P < .05) by 60% and 76% on the LF and HF diets,
respectively. Plasma total cholesterol, TG, and free fatty acid concentrations
also decreased (P < .05). In summary, modified ADF regimens alter adipose tissue 
physiology (ie, body fat distribution, TG metabolism, and adipokines) in a way
that may protect against coronary heart disease. These beneficial effects were
noted over a wide range of fat intake, suggesting that ADF may be protective even
in the presence of HF diets.

PMID: 19375762  [PubMed - indexed for MEDLINE]


23. J Nutr Biochem. 2010 Mar;21(3):188-95. doi: 10.1016/j.jnutbio.2008.11.001. Epub
2009 Feb 5.

Improvements in body fat distribution and circulating adiponectin by
alternate-day fasting versus calorie restriction.

Varady KA, Allister CA, Roohk DJ, Hellerstein MK.

Department of Nutritional Sciences and Toxicology, University of California at
Berkeley, Berkeley, CA 94720, USA. kvarady@nature.berkeley.edu

Calorie restriction (CR) and alternate-day fasting (ADF) beneficially affect
several aspects of adipose tissue physiology, but direct comparisons between
regimens have yet to be performed. The present study evaluated the effects of ADF
versus CR on body fat distribution and circulating adiponectin levels and
examined the kinetic mechanisms that underlie changes in fat distribution. Thirty
female C57BL/6J mice were randomized to one of five groups for 4 weeks: (a)
CR-25% (25% energy restriction daily), (b) ADF-75% (75% restriction on fast day),
(c) ADF-85% (85% restriction on fast day), (d) ADF-100% (100% restriction on fast
day) and (e) control (ad libitum fed). Body weights of the CR mice were lower
than that of the ADF and control groups posttreatment. After 4 weeks of diet, the
proportion of visceral fat decreased (P<.001) and the proportion of subcutaneous 
fat increased (P<.001) similarly in ADF and CR animals. Adiponectin increased
(P<.05) by 62-86% in the ADF groups and by 69% in the CR group. Triglyceride (TG)
synthesis and de novo lipogenesis were augmented (P<.05) in the subcutaneous fat 
pad of ADF and CR animals, relative to control. No differences in net lipolysis
were observed, resulting in greater TG accumulation in the subcutaneous fat pad, 
with a shift in the ratio of TG between depots. These findings indicate that ADF 
(both modified and true) produces similar beneficial modulations in body fat
distribution and adiponectin levels as daily CR.

2010 Elsevier Inc. All rights reserved.

PMID: 19195863  [PubMed - indexed for MEDLINE]


24. Nat Med. 2009 Feb;15(2):159-68. doi: 10.1038/nm.1904. Epub 2009 Jan 11.

AdPLA ablation increases lipolysis and prevents obesity induced by high-fat
feeding or leptin deficiency.

Jaworski K, Ahmadian M, Duncan RE, Sarkadi-Nagy E, Varady KA, Hellerstein MK, Lee
HY, Samuel VT, Shulman GI, Kim KH, de Val S, Kang C, Sul HS.

Department of Nutritional Science and Toxicology, 220 Morgan Hall, University of 
California, Berkeley, California 94720, USA.

A main function of white adipose tissue is to release fatty acids from stored
triacylglycerol for other tissues to use as an energy source. Whereas endocrine
regulation of lipolysis has been extensively studied, autocrine and paracrine
regulation is not well understood. Here we describe the role of the newly
identified major adipocyte phospholipase A(2), AdPLA (encoded by Pla2g16, also
called HREV107), in the regulation of lipolysis and adiposity. AdPLA-null mice
have a markedly higher rate of lipolysis owing to increased cyclic AMP levels
arising from the marked reduction in the amount of adipose prostaglandin E(2)
that binds the Galpha(i)-coupled receptor, EP3. AdPLA-null mice have markedly
reduced adipose tissue mass and triglyceride content but normal adipogenesis.
They also have higher energy expenditure with increased fatty acid oxidation
within adipocytes. AdPLA-deficient ob/ob mice remain hyperphagic but lean, with
increased energy expenditure, yet have ectopic triglyceride storage and insulin
resistance. AdPLA is a major regulator of adipocyte lipolysis and is crucial for 
the development of obesity.

PMCID: PMC2863116
PMID: 19136964  [PubMed - indexed for MEDLINE]


25. Diabetes. 2009 Apr;58(4):855-66. doi: 10.2337/db08-1644. Epub 2009 Jan 9.

Adipose overexpression of desnutrin promotes fatty acid use and attenuates
diet-induced obesity.

Ahmadian M, Duncan RE, Varady KA, Frasson D, Hellerstein MK, Birkenfeld AL,
Samuel VT, Shulman GI, Wang Y, Kang C, Sul HS.

Department of Nutritional Science and Toxicology, University of California,
Berkeley, California, USA.

OBJECTIVE: To investigate the role of desnutrin in adipose tissue triacylglycerol
(TAG) and fatty acid metabolism.
RESEARCH DESIGN AND METHODS: We generated transgenic mice overexpressing
desnutrin (also called adipose triglyceride lipase [ATGL]) in adipocytes
(aP2-desnutrin) and also performed adenoviral-mediated overexpression of
desnutrin in 3T3-L1CARDelta1 adipocytes.
RESULTS: aP2-desnutrin mice were leaner with decreased adipose tissue TAG content
and smaller adipocyte size. Overexpression of desnutrin increased lipolysis but
did not result in increased serum nonesterified fatty acid levels or ectopic TAG 
storage. We found increased cycling between diacylglycerol (DAG) and TAG and
increased fatty acid oxidation in adipocytes from these mice, as well as improved
insulin sensitivity.
CONCLUSIONS: We show that by increasing lipolysis, desnutrin overexpression
causes reduced adipocyte TAG content and attenuation of diet-induced obesity.
Desnutrin-mediated lipolysis promotes fatty acid oxidation and re-esterification 
within adipocytes.

PMCID: PMC2661591
PMID: 19136649  [PubMed - indexed for MEDLINE]


26. Nutrition. 2009 Apr;25(4):486-91. doi: 10.1016/j.nut.2008.10.017. Epub 2008 Dec
11.

Alternate-day fasting reduces global cell proliferation rates independently of
dietary fat content in mice.

Varady KA, Roohk DJ, Bruss M, Hellerstein MK.

Department of Nutritional Sciences and Toxicology, University of California at
Berkeley, Berkeley, California, USA. kvarady@nature.berkeley.edu

OBJECTIVE: Cell proliferation rates represent a central element in the
promotional phase of carcinogenesis. Modified alternate-day fasting (ADF), i.e., 
a partial 24-h fast alternated with 24-h ad libitum feeding, reduces global cell 
proliferation rates on a low-fat (LF) diet. Because the majority of Americans
consume a diet that is high in fat, testing the antiproliferative ability of ADF 
on a high-fat (HF) diet is important in terms of diet tolerability in humans.
Accordingly, we examined the effects of 85% restriction on the fast day (ADF-85%)
with an LF or HF background diet on proliferation rates of various tissues.
METHODS: In a 4-wk study, male C57BL/6J mice were randomized to one of three
groups: 1) ADF-85%-LF, 2) ADF-85%-HF, or 3) control.
RESULTS: Body weights of the ADF mice were similar to that of controls throughout
the study. A hyperphagic response (P < 0.001) was noted only in the ADF-85%-LF
group ( approximately 55% more food consumed on the feed day than controls). No
differences were noted for mean energy intake between ADF groups on feed or fast 
days. Equivalent reductions (P < 0.01) in epidermal, prostate, liver, and splenic
T-cell proliferation rates were observed in both ADF groups versus controls.
Plasma insulin-like growth factor-1 levels decreased (P < 0.05) similarly in both
ADF groups. Insulin-like growth factor-1 mRNA levels were not affected by either 
treatment.
CONCLUSION: These findings indicate that ADF has an antiproliferative effect over
a wide range of fat intakes, which may enhance adherence to ADF in humans.

PMID: 19084375  [PubMed - indexed for MEDLINE]


27. Nutr Rev. 2008 Jun;66(6):333-42. doi: 10.1111/j.1753-4887.2008.00041.x.

Do calorie restriction or alternate-day fasting regimens modulate adipose tissue 
physiology in a way that reduces chronic disease risk?

Varady KA, Hellerstein MK.

Department of Nutritional Sciences and Toxicology, University of California at
Berkeley, Berkeley, California 94720-3104, USA. kvarady@nature.berkeley.edu

Adipose tissue physiology plays an important role in the development of several
obesity-related disorders. Dietary restriction regimens, i.e., daily calorie
restriction (CR) or alternate-day fasting (ADF), have been shown to decrease the 
risk of these disorders. Whether changes in adipose mass or physiology are
required for the beneficial effects of CR or ADF is an important question.
Accordingly, this review summarizes the effects of CR and ADF regimens on
parameters of adipose physiology, i.e., adipose tissue morphology, triglyceride
metabolism, and adipokine release, and attempts to link these changes to
indicators of chronic disease risk.

PMID: 18522622  [PubMed - indexed for MEDLINE]


28. Appl Physiol Nutr Metab. 2008 Feb;33(1):118-23. doi: 10.1139/H07-134.

Are functional foods redefining nutritional requirements?

Jones PJ, Varady KA.

Richardson Centre for Functional Foods and Nutraceuticals, University of
Manitoba, 196 Innovation Dr., Winnipeg, MB R3T 6C5. peter_jones@umanitoba.ca

Functional foods are increasing in popularity owing to their ability to confer
health and physiological benefits. Nevertheless, the notion that functional foods
improve health when providing nutrients at levels above and beyond existing
recommended intakes is inconsistent with the definition of requirement. This
disparity highlights the need for an alternative definition of nutrient
requirement. The present objective is to examine distinctions between
optimization of health, as defined by what we currently deem as required intakes,
versus adding physiological benefit using bioactive agents found in functional
foods. Presently, requirement is defined as the lowest amount of intake of a
nutrient that will maintain a defined level of nourishment for a specific
indicator of adequacy. In contrast, functional foods are described as ingredients
that are not necessary for body function, yet provide added physiological benefit
that confer better overall health. Plant sterols are one example of such an
ingredient. Plant sterols lower plasma cholesterol concentrations, and may thus
be considered essential nutrients in physiological situations where circulating
cholesterol concentrations are high. Similarly, intakes of omega-3 fats beyond
existing requirement may confer additional health benefits such as hypolipidemic 
and anti-diabetic effects. These examples underscore the inconsistencies between 
what is defined as a nutrient requirement versus what is identified as a health
benefit of a functional food. Such discrepancies emphasize the need for a more
all-encompassing definition of a nutrient requirement; that is, one that moves
beyond the prevention of overt deficiency to encompass improved health and
disease risk reduction.

PMID: 18347661  [PubMed - indexed for MEDLINE]


29. FASEB J. 2008 Jun;22(6):2090-6. doi: 10.1096/fj.07-098178. Epub 2008 Jan 9.

Modified alternate-day fasting regimens reduce cell proliferation rates to a
similar extent as daily calorie restriction in mice.

Varady KA, Roohk DJ, McEvoy-Hein BK, Gaylinn BD, Thorner MO, Hellerstein MK.

Department of Nutritional Sciences and Toxicology, University of California at
Berkeley, Morgan Hall, Rm. 308, Berkeley, California, 94720-3104, USA.
kvarady@nature.berkeley.edu

Calorie restriction (CR) and alternate-day fasting (ADF) reduce cancer risk and
reduce cell proliferation rates. Whether modified ADF regimens (i.e., allowing a 
portion of energy needs to be consumed on the fast day) work, as well as true ADF
or CR to reduce global cell proliferation rates, remains unresolved. Here, we
measured the effects of true ADF, modified ADF, and daily CR on cell
proliferation rates in mice. Thirty female C57BL/6J mice were randomized to one
of five interventions for 4 wk: 1) CR-25% (25% reduction in daily energy intake),
2) ADF-75% (75% reduction on fast day), 3) ADF-85% (85% reduction on fast day),
4) ADF-100% (100% reduction on fast day), and 5) control (ad libitum intake).
Body weights of the ADF groups did not differ from controls, whereas the CR-25%
group weighed less than all other groups posttreatment. Epidermal cell
proliferation decreased (P<0.01) by 29, 20, and 31% in the CR-25%, ADF-85% and
ADF-100% groups, respectively, relative to controls. Proliferation rates of
splenic T cells were reduced (P<0.01) by 37, 32, and 31% in the CR-25%, ADF-85%, 
and ADF-100% groups, respectively, and mammary epithelial cell proliferation was 
70, 65, and 62% lower (P<0.01), compared with controls. Insulin-like growth
factor-1 levels were reduced (P<0.05) in the CR-25% and ADF-100% groups only. In 
summary, modified ADF, allowing the consumption of 15% of energy needs on the
restricted intake day, decreases global cell proliferation similarly as true ADF 
and daily CR without reducing body weight.

PMCID: PMC2975447
PMID: 18184721  [PubMed - indexed for MEDLINE]


30. Can J Physiol Pharmacol. 2007 Sep;85(9):903-10.

Modulation of apolipoprotein A1 and B, adiponectin, ghrelin, and growth hormone
concentrations by plant sterols and exercise in previously sedentary humans.

Collins M, Varady KA, Jones PJ.

School of Dietetics and Human Nutrition, McGill University, Ste-Anne-de-Bellevue,
Montreal, QC H9X3V9, Canada.

Plant sterols combined with exercise beneficially alter lipid levels in
hypercholesterolemic adults. The effect of this combination therapy on other
indicators of coronary heart disease risk, however, has yet to be determined. The
objective of this trial was to investigate the effect of plant sterols and
exercise, alone and in combination, on levels of apolipoprotein (apo) A1 and B,
adiponectin, ghrelin, and growth hormone in previously sedentary
hypercholesterolemic adults. In an 8 week, parallel-arm trial, 84 subjects were
randomized to 1 of 4 groups: combination, exercise, plant sterols, or control.
Body mass decreased by 1.1% (p < 0.01) and 0.9% (p < 0.05) in the combination and
exercise group, respectively. Low-density lipoprotein cholesterol levels
decreased (p < 0.01) by 0.30 mmol/L in the combination group and by 0.49 mmol/L
in the plant sterol group. High-density lipoprotein cholesterol levels increased 
by 7.5% and 9.5% (p < 0.01) in the combination and exercise groups, respectively.
Plant sterols increased (p < 0.05) adiponectin levels by 16%. No change in apoA1,
apoB, ghrelin, or growth hormone levels were noted in any intervention group.
ApoA1 was correlated with high-density lipoprotein cholesterol (r = 0.33, p =
0.01), whereas apoB was weakly related to low-density lipoprotein cholesterol
levels (r = 0.13, p = 0.002). Adiponectin was associated with body mass index (r 
= -0.10, p = 0.006) and high-density lipoprotein cholesterol (r = 0.17, p =
0.0003). These findings suggest that plant sterols can increase adiponectin
levels, thereby possibly reducing the risk of future coronary heart disease.

PMID: 18066136  [PubMed - indexed for MEDLINE]


31. Am J Clin Nutr. 2007 Jul;86(1):7-13.

Alternate-day fasting and chronic disease prevention: a review of human and
animal trials.

Varady KA, Hellerstein MK.

Department of Nutritional Sciences and Toxicology, University of California at
Berkeley, Berkeley, CA 94720-3104, USA. kvarady@nature.berkeley.edu

Calorie restriction (CR) and alternate-day fasting (ADF) represent 2 different
forms of dietary restriction. Although the effects of CR on chronic disease
prevention were reviewed previously, the effects of ADF on chronic disease risk
have yet to be summarized. Accordingly, we review here animal and human evidence 
concerning ADF and the risk of certain chronic diseases, such as type 2 diabetes,
cardiovascular disease, and cancer. We also compare the magnitude of risk
reduction resulting from ADF with that resulting from CR. In terms of diabetes
risk, animal studies of ADF find lower diabetes incidence and lower fasting
glucose and insulin concentrations, effects that are comparable to those of CR.
Human trials to date have reported greater insulin-mediated glucose uptake but no
effect on fasting glucose or insulin concentrations. In terms of cardiovascular
disease risk, animal ADF data show lower total cholesterol and triacylglycerol
concentrations, a lower heart rate, improved cardiac response to myocardial
infarction, and lower blood pressure. The limited human evidence suggests higher 
HDL-cholesterol concentrations and lower triacylglycerol concentrations but no
effect on blood pressure. In terms of cancer risk, there is no human evidence to 
date, yet animal studies found decreases in lymphoma incidence, longer survival
after tumor inoculation, and lower rates of proliferation of several cell types. 
The findings in animals suggest that ADF may effectively modulate several risk
factors, thereby preventing chronic disease, and that ADF may modulate disease
risk to an extent similar to that of CR. More research is required to establish
definitively the consequences of ADF.

PMID: 17616757  [PubMed - indexed for MEDLINE]


32. J Lipid Res. 2007 Oct;48(10):2212-9. Epub 2007 Jul 2.

Effects of modified alternate-day fasting regimens on adipocyte size,
triglyceride metabolism, and plasma adiponectin levels in mice.

Varady KA, Roohk DJ, Loe YC, McEvoy-Hein BK, Hellerstein MK.

Department of Nutritional Sciences and Toxicology, University of California at
Berkeley, Berkeley, CA 94720, USA. kvarady@nature.berkeley.edu

Calorie restriction (CR) affects adipocyte function and reduces body weight.
However, the effects of alternate-day fasting (ADF) on adipose biology remain
unclear. This study examined the effects of ADF and modified ADF regimens on
adipocyte size, triglyceride (TG) metabolism, and adiponectin levels in relation 
to changes in body weight and adipose mass. Twenty-four male C57BL/6J mice were
randomized for 4 weeks among 1) ADF-25% (25% CR on fast day, ad libitum on
alternate day), 2) ADF-50% (50% CR on fast day), 3) ADF-100% (100% CR on fast
day), and 4) control (ad libitum). The body weight of ADF-100% mice was lower
than that of the other groups (P < 0.005) after treatment. Adipose tissue weights
did not change. Inguinal and epididymal fat cells were 35-50% smaller (P < 0.01) 
than those of controls in ADF-50% and ADF-100% animals after treatment. Net
lipolysis was augmented (P < 0.05) in ADF-100% mice, and the contribution from
glyceroneogenesis to alpha-glycerol phosphate increased in ADF-50% and ADF-100%
mice, whereas fractional and absolute de novo lipogenesis also increased in
ADF-50% and ADF-100% animals, consistent with an alternating feast-fast milieu.
Plasma adiponectin levels were not affected. In summary, modified ADF (ADF-50%)
and complete ADF (ADF-100%) regimens modulate adipocyte function, despite there
being no change in body weight or adipose tissue weight in the former group.

PMID: 17607017  [PubMed - indexed for MEDLINE]


33. J Appl Physiol (1985). 2007 Aug;103(2):547-51. Epub 2007 May 10.

Dose effects of modified alternate-day fasting regimens on in vivo cell
proliferation and plasma insulin-like growth factor-1 in mice.

Varady KA, Roohk DJ, Hellerstein MK.

Department of Nutritional Sciences and Toxicology, University of California at
Berkeley, Berkeley, California 94720-3104, USA. kvarady@nature.berkeley.edu

Reduced cell proliferation is associated with lower cancer risk. Alternate-day
fasting (ADF), defined as alternating 24-h periods of ad libitum feeding and
fasting, decreases cell proliferation. The effect of modified regimens of ADF on 
cell proliferation, however, has not been examined. This study measured the
effects of modified ADF regimens on prostate and splenic T-cell proliferation and
circulating insulin-like growth factor-1 (IGF-1) levels in mice. In a 4-wk study,
24 male C57BL/6J mice were randomized to one of four interventions: 1) ADF-25%
[25% calorie restriction (CR) on fast day], 2) ADF-50% (50% CR on fast day), 3)
ADF-100% (100% CR on fast day), and 4) control. Body weight of the ADF-100% group
was less (P < 0.005) than that of the ADF-25% and ADF-50% groups posttreatment.
On the feast day, the ADF-100% and ADF-50% groups ate 85% and 45% more food,
respectively, than controls, indicating a hyperphagic response to fasting.
Proliferation rates of T-cells were 6% and 30% lower (P < 0.05) in the ADF-50%
and ADF-100% groups, respectively, relative to controls. Prostate cell
proliferation was reduced (P < 0.05) by 49% in the ADF-100% group, relative to
controls, but did not change in the other groups. IGF-1 levels were reduced (P < 
0.05) by 40%, relative to controls, in the ADF-100% group. These findings confirm
the beneficial effects of ADF-100% on cancer risk by decreasing cell
proliferation and IGF-1 levels and suggest that modified ADF regimens comprising 
25-50% CR on the fast day do not replicate these effects.

PMID: 17495119  [PubMed - indexed for MEDLINE]


34. Am J Hum Biol. 2007 May-Jun;19(3):429-33.

Validation of hand-held bioelectrical impedance analysis with magnetic resonance 
imaging for the assessment of body composition in overweight women.

Varady KA, Santosa S, Jones PJ.

School of Dietetics and Human Nutrition, McGill University, Québec, Canada.

Methods of assessing body composition suitable for use in clinical trials should 
be accurate, reliable, and easy to perform. One such technique routinely
implemented is hand-held bioelectrical impedance analysis (BIA). The validity of 
this method, however, in body composition assessment of overweight women is not
known. The aim of this study was to validate the hand-held BIA technique with
magnetic resonance imaging (MRI) for the assessment of body composition in
overweight women. Fat mass, percent fat mass, fat-free mass, and percent fat-free
mass values estimated by hand-held BIA were compared to those measured by MRI.
Thirty-one Caucasian women (50.1 +/- 8.2 years, body mass index of 26.9 +/- 3.1
kg/m(2)) participated in the study. BIA measurements were highly reproducible
(technical error (TE) was 0.06 +/- 0.07 kg for fat mass and 0.08 +/- 0.11% for
percent fat mass), but were significantly different (P < 0.0001) for each body
composition parameter when compared to MRI. BIA underestimated fat mass by 2.3
+/- 3.3 kg and percent fat mass by 5.6 +/- 3.9%. Likewise, BIA overestimated fat 
free mass by 7.4 +/- 2.7 kg and percent fat free mass by 5.6 +/- 3.2%. No
relationship between the bias and the mean of the two measurements was noted
suggesting that bias is not related to measurement size. Although hand-held BIA
gives reproducible findings, the bias noted for all body composition parameters
puts into question the validity of this regional impedance device for use in
clinical trials in overweight women.

Copyright 2007 Wiley-Liss, Inc.

PMID: 17421003  [PubMed - indexed for MEDLINE]


35. Transl Res. 2007 Jan;149(1):22-30.

Effect of plant sterols and exercise training on cholesterol absorption and
synthesis in previously sedentary hypercholesterolemic subjects.

Varady KA, Houweling AH, Jones PJ.

School of Dietetics and Human Nutrition, Faculty of Agricultural and
Environmental Sciences, McGill University, Montreal, Quebec, Canada.

Plant sterols combined with exercise beneficially alter lipid profiles in
hypercholesterolemic adults. Although the mechanism by which plant sterols
favorably modulate lipid levels is well established, no trial to date has
examined the effect of exercise, alone or combined with plant sterols, on
cholesterol kinetics. Thus, the current objective was to examine the effects of
exercise, plant sterols, and the combination of exercise and plant sterols on
cholesterol absorption and synthesis. In an 8-week, parallel-arm trial, 84
subjects were randomized to 1 of 4 interventions: plant sterols combined with
exercise, plant sterols, exercise, or control. Diets were not controlled. Total
cholesterol and triglyceride levels decreased (P<0.01) by 7.7% and 11.8%,
respectively, whereas high-density lipoprotein (HDL) cholesterol levels increased
(P<0.01) by 7.5% in the combination group. Mean posttreatment low-density
lipoprotein (LDL) cholesterol levels decreased (P<0.01) by 0.30 mmol/L in the
combination group. Cholesterol absorption was 16% lower (P<0.01) in the
combination group and 18% lower (P<0.01) in the plant sterol group, when compared
with control. Exercise had no effect on cholesterol absorption. Nonsignificant
increases in cholesterol synthesis rates of 63% (0.084+/-0.014 pools/day), 59%
(0.075+/-0.013 pools/day), and 57% (0.072+/-0.011 pools/day) were observed in the
combination, exercise, and plant sterol groups, respectively, relative to the
control group (0.031+/-0.019 pools/day). LDL cholesterol levels correlated with
cholesterol absorption, as represented by the area under the deuterium enrichment
curve (r=0.23, P=0.05), and with percent absorption relative to control (r=0.25, 
P=0.03). These findings suggest that exercise does not modulate lipid levels by
altering to cholesterol absorption or synthesis, whereas plant sterols favorably 
alter levels of LDL cholesterol by suppressing intestinal absorption.

PMID: 17196519  [PubMed - indexed for MEDLINE]


36. Life Sci. 2007 Jan 16;80(6):505-14. Epub 2006 Oct 17.

Physiological and therapeutic factors affecting cholesterol metabolism: does a
reciprocal relationship between cholesterol absorption and synthesis really
exist?

Santosa S, Varady KA, AbuMweis S, Jones PJ.

School of Dietetics and Human Nutrition, McGill University, Montreal, Quebec,
Canada.

Cholesterol absorption and synthesis contribute to maintaining cholesterol
homeostasis. Several physiological and therapeutic factors affect cholesterol
homeostasis, including: genetics, circadian rhythm, body weight, plant sterols,
ezetimibe, and statin therapy. The present objective is to determine the main
vector, i.e. cholesterol absorption or synthesis, affected by each of these
factors, and to examine whether an alteration in one vector is linked to a
reciprocal change in the other. Current techniques used to assess cholesterol
absorption and synthesis are also reviewed. Review of physiological factors
affecting cholesterol metabolism suggest a reciprocal relationship between these 
two vectors. Carriers of the E2 isoform of apolipoprotein E and ATP binding
cassette (ABC) G8 19H (exon 1 mutation) show a decrease in cholesterol absorption
accompanied by a corresponding increase in synthesis. Circadian rhythm affects
cholesterol synthesis, however, its effect on absorption has yet to be
established. Obese subjects show an increase in cholesterol synthesis with a
subsequent decrease in cholesterol absorption. Weight loss down regulates
cholesterol synthesis, but has little or no effect on absorption. In the case of 
therapeutic factors, plant sterols and stanols inhibit cholesterol absorption,
which results in a compensatory increase in synthesis. Ezetimibe also decreases
intestinal absorption, while reciprocally increasing synthesis. Statin therapy
down regulates synthesis, which is accompanied by a rise in absorption. These
findings suggest that a change in one vector, fairly consistently, results in a
compensatory and opposing change in the other. An understanding of this
reciprocal relationship between cholesterol absorption and synthesis may allow
for the development of more effective interventions for dyslipidemic disorders.

PMID: 17113605  [PubMed - indexed for MEDLINE]


37. Nutr Rev. 2006 Sep;64(9):385-402.

Plasma concentrations of plant sterols: physiology and relationship with coronary
heart disease.

Chan YM, Varady KA, Lin Y, Trautwein E, Mensink RP, Plat J, Jones PJ.

School of Dietetics and Human Nutrition, McGill University, 21,111 Lakeshore
Road, Ste. Anne de Bellevue, Québec, Canada H9X 3V9.

Recently, it has been questioned whether elevated levels of circulating plant
sterols increase the risk of coronary heart disease (CHD). To date, no definitive
conclusions regarding such a relationship have been reached, nor have there been 
any studies summarizing the factors that contribute to the observed elevations in
plant sterol concentrations in plasma. Thus, the purpose of this review is to
systematically compare the plant sterol levels of subjects from the general
population and to describe factors that contribute to the variations observed.
The question of whether elevated plasma concentrations of plant sterols are
associated with an increased risk of CHD was also assessed. Results indicate that
the key factors accounting for variations in circulating plant sterol
concentrations include: apolipoprotein E phenotypes, ATP-binding cassette
transporter polymorphisms, use of statin drugs, presence of metabolic syndrome,
dietary intake of plant sterols, gender, and analytical techniques used in the
measurement of plant sterols in the plasma. An analysis of the studies examining 
the relationship between circulating levels of plant sterols and CHD risk in
non-sitosterolemic populations revealed no clear associations. Furthermore, it
was shown that the above-mentioned factors play an important role in determining 
the levels of plant sterols in plasma. Since these factors may act as potential
confounders, they must be controlled for before more solid conclusions can be
reached.

PMID: 17002235  [PubMed - indexed for MEDLINE]


38. Metabolism. 2006 Oct;55(10):1302-7.

Effect of weight loss resulting from a combined low-fat diet/exercise regimen on 
low-density lipoprotein particle size and distribution in obese women.

Varady KA, Lamarche B, Santosa S, Demonty I, Charest A, Jones PJ.

School of Dietetics and Human Nutrition, McGill University, Montreal, Quebec,
Canada, H9X 3V9.

Weight loss resulting from diet interventions has been shown to favorably affect 
low-density lipoprotein (LDL) particle size and distribution, and, hence,
decrease cardiovascular disease risk. However, the effect of a dietary weight
loss strategy when combined with exercise, on LDL electrophoretic
characteristics, has yet to be tested. This study examined the effect of a weight
loss intervention that combined a low-fat diet with moderate endurance training, 
on LDL particle size and distribution in obese women. Thirty obese,
hypercholesterolemic women participated in a controlled longitudinal weight loss 
trial, which consisted of (1) a 2-week pre-stabilization phase, (2) a 20-week
weight loss phase, and (3) a 2-week post-stabilization phase. Weight reduction
resulted from a low-fat diet (<30% fat, 50%-60% carbohydrate, 20% protein)
combined with an endurance training program (>40 minutes moderate training, 3
times per week). Mean weight loss was 14.8% (P < .01) of initial body weight.
Total, LDL cholesterol, and triacylglycerol concentrations decreased (P < .01) by
8.9%, 7.5%, and 27.1%, respectively, whereas high-density lipoprotein cholesterol
concentrations increased (P < .01) by 9.9%. No significant differences were noted
for LDL peak or integrated particle size. The relative proportion of small,
medium, and large particles was not significantly different posttreatment.
Estimated cholesterol concentrations in large- and medium-sized LDL particles
decreased (P < .05) by 15.3% and 5.9%, respectively, as a result of weight loss. 
No effect was noted for estimated cholesterol concentrations in small size LDL
particles. In conclusion, these findings suggest that weight loss, resulting from
a low-fat diet/exercise program, has only a minimal effect on LDL particle size
and distribution.

PMID: 16979399  [PubMed - indexed for MEDLINE]


39. J Nutr Biochem. 2006 Apr;17(4):217-24. Epub 2005 Oct 10.

Plant sterols combined with exercise for the treatment of hypercholesterolemia:
overview of independent and synergistic mechanisms of action.

Marinangeli CP, Varady KA, Jones PJ.

School of Dietetics and Human Nutrition, McGill University, Québec, Canada.

At present, dyslipidemia is most commonly treated with lipid-altering
pharmacological therapies. However, safety concerns regarding the use of these
agents have prompted the need for safe and efficacious nonpharmacological
lipid-altering interventions. One such natural therapy is the combination of
plant sterols and endurance training. This combination lifestyle intervention has
been shown to decrease total cholesterol, low-density lipoprotein (LDL)
cholesterol and triglyceride concentrations while increasing high-density
lipoprotein (HDL) cholesterol concentrations. However, the mechanisms that
underlie these positive lipid alterations have yet to be clarified. Thus, the
purpose of this review is to evaluate individual effects of plant sterols and
exercise training on lipid levels while attempting to elucidate the possible
independent and synergistic mechanisms of action responsible for these
modulations. Results reveal that plant sterols decrease both total and LDL
cholesterol levels by reducing exogenous cholesterol absorption by way of
cholesterol displacement in the intestinal lumen. Additionally, the intestinal
membrane transport proteins, ABCG5, ABCG8, as well as NPC1L1, have also been
implicated in plant sterol-mediated cholesterol lowering. Conversely, exercise
decreases triglyceride levels by reducing hepatic very low-density lipoprotein
secretion and increasing skeletal lipoprotein lipase activity. In addition,
endurance training was shown to increase HDL cholesterol levels by way of HDL
subfraction alterations, in conjunction with changing reverse cholesterol
transport enzyme activities. Moreover, plant sterols and exercise may work
synergistically to alter lipid levels by modulating lipoprotein transport,
composition, release and metabolism. In sum, the present review lends further
insight as to the metabolic benefits of adopting a healthy lifestyle, including
plant sterols and endurance training, in the treatment of dyslipidemia.

PMID: 16410048  [PubMed - indexed for MEDLINE]


40. J Nutr. 2005 Aug;135(8):1829-35.

Combination diet and exercise interventions for the treatment of dyslipidemia: an
effective preliminary strategy to lower cholesterol levels?

Varady KA, Jones PJ.

School of Dietetics and Human Nutrition, McGill University, Ste. Anne de
Bellevue, QC, Canada.

At present, dyslipidemia is most commonly treated with drug therapy. However,
because safety concerns regarding the use of pharmaceutical agents have arisen, a
need for alternative nonpharmacological therapies has become increasingly
apparent. The National Cholesterol Education Program (NCEP) Adult Treatment Panel
III (ATP III) recommends lifestyle therapies, which include a combination of diet
and exercise modifications, in place of drug treatment for patients who fall into
an intermediate range of coronary heart disease (CHD) risk. This review examined 
the cholesterol lowering efficacy of the following 2 NCEP-recommended combination
therapies: 1) low saturated fat diets combined with exercise, and 2) nutritional 
supplementation, i.e., fish oil, oat bran, or plant sterol supplementation,
combined with exercise, in the treatment of dyslipidemia. Combination therapies
are particularly advantageous because diet and exercise elicit complementary
effects on lipid profiles. More specifically, diet therapies, with some
exceptions, lower total (TC) and LDL cholesterol (LDL-C) concentrations, whereas 
exercise interventions increase HDL cholesterol (HDL-C) while decreasing
triglyceride (TG) levels. With respect to specific interventions, low saturated
fat diets combined with exercise lowered TC, LDL-C, and TG concentrations by
7-18, 7-15, and 4-18%, respectively, while increasing HDL-C levels by 5-14%.
Alternatively, nutritional supplements combined with exercise, decreased TC,
LDL-C, and TG concentrations by 8-26, 8-30, and 12-39%, respectively, while
increasing HDL-C levels by 2-8%. These findings suggest that combination
lifestyle therapies are an efficacious, preliminary means of improving
cholesterol levels in those diagnosed with dyslipidemia, and should be
implemented in place of drug therapy when cholesterol levels fall just above the 
normal range.

PMID: 16046704  [PubMed - indexed for MEDLINE]


41. Eur J Clin Nutr. 2005 Apr;59(4):518-25.

Effect of plant sterols and endurance training on LDL particle size and
distribution in previously sedentary hypercholesterolemic adults.

Varady KA, St-Pierre AC, Lamarche B, Jones PJ.

School of Dietetics and Human Nutrition, McGill University, Ste. Anne de
Bellevue, Québec, Canada H9X 3V9.

BACKGROUND: Plant sterols and exercise favourably alter lipid profiles in a way
that protect against future coronary heart disease (CHD). However, their effects 
on other indicators of CHD risk, such as LDL particle size, still need further
clarification.
OBJECTIVE: This study examined the effect of plant sterols, exercise, and the
combination of plant sterols and exercise, on LDL particle size and distribution 
in previously sedentary, hypercholesterolemic adults.
DESIGN: In an 8-week, placebo-controlled, parallel-arm clinical trial, 84
subjects were randomized to one of four intervention groups: (1) combination of
sterols and exercise, (2) exercise, (3) sterol, or (4) control.
RESULTS: Exercise significantly (P < 0.05) reduced post-treatment LDL peak
particle size from 255 to 253 A. Additionally, exercise significantly (P < 0.05) 
decreased the proportion of large LDL particles within plasma. Sterol
supplementation significantly (P < 0.05) decreased the estimated cholesterol
concentrations within small, medium, and large LDL particles by 13.4, 13.5, and
14.4%, respectively, yet had no effect on the distribution of cholesterol among
various LDL particle sizes. Furthermore, decreased body weight post-training was 
associated with increased cholesterol in small LDL particles (r = -0.52, P <
0.0001). Decrease in body fat percent (BF%) post-training was associated with
increased cholesterol concentrations in small LDL particles (r = -0.29, P <
0.01).
CONCLUSION: On the basis of modulating LDL electrophoretic characteristics, the
present study demonstrates that plant sterols have no effect on CHD risk, while
short-term exercise may potentially increase CHD risk by decreasing LDL peak
particle size.
SPONSORSHIP: This study was sponsored by The Heart and Stroke Foundation of
Canada.

PMID: 15674305  [PubMed - indexed for MEDLINE]


42. Am J Clin Nutr. 2004 Nov;80(5):1159-66.

Plant sterols and endurance training combine to favorably alter plasma lipid
profiles in previously sedentary hypercholesterolemic adults after 8 wk.

Varady KA, Ebine N, Vanstone CA, Parsons WE, Jones PJ.

School of Dietetics and Human Nutrition, Faculty of Agricultural and
Environmental Sciences, McGill University, Montreal, and the Veterans' Hospital, 
Sainte Anne de Bellevue, Quebec.

BACKGROUND: Plant sterol supplementation was shown to reduce total and
LDL-cholesterol concentrations, whereas endurance training was shown to increase 
HDL-cholesterol concentrations and decrease triacylglycerol concentrations.
OBJECTIVE: The objective was to examine the effect of plant sterols, endurance
training, and the combination of plant sterols and endurance training on plasma
lipid and lipoprotein cholesterol concentrations, sterol concentrations, and
cholesterol precursor concentrations in previously sedentary hypercholesterolemic
adults.
DESIGN: In an 8-wk, placebo-controlled, parallel-arm clinical trial, 84 subjects 
were randomly assigned to receive 1 of 4 interventions: 1) combination of sterols
and exercise, 2) exercise, 3) sterols, or 4) control treatment.
RESULTS: Sterol supplementation significantly (P < 0.01) decreased total
cholesterol concentrations by 8.2% from baseline. In addition, sterols
significantly (P < 0.01) lowered absolute LDL-cholesterol concentrations after
treatment but had no effect on the percentage change from the beginning to the
end of the trial. Exercise significantly (P < 0.01) increased HDL-cholesterol
concentrations by 7.5% and decreased triacylglycerol concentrations by 13.3% from
baseline. Moreover, sterol supplementation significantly (P < 0.05) increased
lathosterol, campesterol, and beta-sitosterol concentrations after treatment.
Exercise significantly (P < 0.01) decreased percentage of body fat by 3.9% from
the beginning to the end of the trial.
CONCLUSIONS: In comparison with plant sterols or exercise alone, the combination 
of plant sterols and exercise yields the most beneficial alterations in lipid
profiles. Implementation of such a combination therapy could improve lipid
profiles in those at risk of coronary artery disease.

PMID: 15531661  [PubMed - indexed for MEDLINE]


43. Nutr Rev. 2003 Nov;61(11):376-83.

Role of policosanols in the prevention and treatment of cardiovascular disease.

Varady KA, Wang Y, Jones PJ.

School of Dietetics and Human Nutrition, McGill University, Ste-Anne-de-Bellevue,
Québec, Canada.

Policosanols are a mixture of aliphatic alcohols derived from purified sugar
cane. When administered at 5 to 20 mg/day, policosanols have been shown to
decrease the risk of atheroma formation by reducing platelet aggregation,
endothelial damage, and foam cell formation in animals. Additionally,
policosanols have been shown to lower total and low-density lipoprotein (LDL)
cholesterol levels by 13 to 23% and 19 to 31%, respectively, while increasing
high-density lipoprotein (HDL) cholesterol from 8 to 29%. Policosanols are
thought to improve lipid profiles by reducing hepatic cholesterol biosynthesis
while enhancing LDL clearance. When compared with statins, policosanols exhibit
comparable cholesterol-lowering effects at much smaller doses. The mixture is
well tolerated when administered to animals; however, a more precise safety
profile is needed for humans. In summary, policosanols are a promising resource
in the prevention and therapy of cardiovascular disease (CVD), but these results 
need to be confirmed in independent laboratories.

PMID: 14677572  [PubMed - indexed for MEDLINE]