Some CRers lose no weight?

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Hi All,

Do some CRers lose no weight? It seems that 0.125 or one in eight CRers

did not. Adherence to the CR is one issue the report, which is

pdf-available, did not present data.

Corella D, Qi L, Sorli JV, Godoy D, Portoles O, Coltell O, Greenberg AS,

Ordovas JM.

Obese subjects carrying the 11482G>A polymorphism at the perilipin (PLIN)

locus are resistant to weight loss following dietary energy restriction.

J Clin Endocrinol Metab. 2005 Jun 28; [Epub ahead of print]

PMID: 15985482

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstra\

ct & list_uids=15985482 & query_hl=8

INTRODUCTION

In addition to the current obesogenic environment, genetic factors play a

significant role in the predisposition of individuals to developing

obesity and, potentially,

to the successful outcome of current therapies (1,2). Therefore, treatment

strategies could

be dramatically improved if predictive information about the response of

the obese

subject to therapy (i.e., energy restriction) was available. However,

before nutritional

genomics is in a position to contribute significantly to treatment of

obese patients,

substantial work has to be done to identify relevant genetic variants and

their specific

dietary interactions (3).

In this regard, adipose tissue plays a central role in regulating the

storage and

mobilization of energy, and it has been the focus of efforts to identify

candidate genes for

obesity and weight management. Perilipins are phosphorylated proteins in

adipocytes that

are localized at the surface of the lipid droplet (4,5). Experimental

studies have shown

that these proteins are essential in the regulation of triglycerides

deposition and

mobilization (6-8). After activation of protein kinase A, perilipin is

phosphorylated,

resulting in translocation of the protein away from the lipid droplet and

allows hormone-sensitive

lipase to hydrolyze the adipocyte triglycerides to release nonesterified

fatty

acids (9,10). Perilipin functions to increase cellular triglycerides

storage by decreasing

the rate of triglycerides hydrolysis and serves an additional role in

controlling the release

of triglycerides at times of need. Two independent laboratories produced

perilipin

knockout mice (11, 12), and shown that these animals were lean, had

increased basal

lipolysis, and were resistant to diet-induced obesity. A recent study

examining perilipin

expression in humans, have found that perilipin was elevated in obese

subjects (13).

Moreover, in the first large population-based study we have demonstrated

that variations

at the perilipin (PLIN) locus are associated with obesity risk (14). These

findings

prompted us to initiate the present study aimed to analyze the influence

of PLIN

polymorphisms on anthropometrical measures in massively obese subjects as

well as to

examine the potential gene-diet interaction between PLIN polymorphisms and

an energy-restricted

diet on the ability to lose weight during a 1-year follow-up intervention.

SUBJECTS AND METHODS

Patients and study design

The present study included 150 obese patients (29 men and 121 women aged

18-

68 years) referred to the Endocrinology Unit of the University General

Hospital in

Valencia, Spain for diagnostic and weight reduction treatments related to

obesity. These

patients were randomly selected among those obese subjects referred

consecutively from

May 2001 to September 2002, and who had normal thyroid function and no

concomitant

renal, hepatic, cardiac disease or Cushing disease. Pregnant or nursing

women were also

excluded. Sixty-two women (51%) were postmenopausal. All patients were

Caucasian

and the mean age was 48 +/- 14 years. Body mass index (BMI) ranged from 30

to 79 Kg/m^2,

with 88% of patients having a BMI ¡Ã35Kg/m^2.

.... Weight reduction treatments including diet, drugs or surgery

were recommended to each obese patient according to standard clinical

guidelines (20).

Bariatric surgery (21) was recommended to 13 patients. Forty-two patients

received

weight-loss medications (orlistat, sibutramine, antidepressants, or fiber)

combined with

diet, and 92 patients were prescribed to receive an energy-restricted

diet. Patients

assigned to the energy-restricted diet with no medication for weight loss

(61% of patient

at baseline) were invited to participate in the one-year follow-up study

to investigate if

PLIN polymorphisms modulate the weight loss in response to diet. As PLIN

genotypes in

these patients were determined at the end of the follow-up, the design of

this study can

be classified as a double-blinded paralleled randomized trial because no

one had previous

information about the group assignment. The randomization of individuals

is provided by

Mendelian randomization, the term applied to the random assortment of

alleles at the

time of gamete formation (22).

Dietary intervention

Forty-eight motivated patients (9 men and 39 women) completed the one-year

dietary follow-up treatment and had complete dataset at each time point.

All patients

started with a 2-weeks very-low energy diet (Modifast; NOVARTIS Nutrition,

Bern,

Switzerland) providing 603 Kcal/day (lipids: 13.5 g, proteins: 52.5 g and

carbohydrates:

67.5 g) under highly controlled hospital conditions. Thereafter,

conventional food was

introduced and patients were advised from a registered dietician to

consume a standard

hypocaloric diet with an energy content being approximately 1200 kcal/day

(lipids: 52 g,

proteins: 62 g, and carbohydrates: 121 g) for one year. The patients were

given dietary

instructions based on an education system consisting of isoenergetic

interchangeable

units. Three follow-up evaluations were performed at 3, 6 and 12 months.

All evaluations

were conducted at the Endocrinology Unit of the University General

Hospital. Adherence

to diet was confirmed in these evaluations. None of the obese patients was

involved in an

exercise program.

.... RESULTS

At baseline, 150 obese patients (29 men and 121 women) were studied. Mean

age

was 48¡¾14 years in both men and women. No statistically significant

differences in mean

BMI (42¡¾8 kg/m 2 ) were observed by gender. PLIN genotypes were

determined in these

patients. As no heterogeneity by gender was detected, data for men and

women were

analyzed together and results presented gender-adjusted. Genotype

distributions did not

deviate from Hardy-Weinberg expectations for any SNP. The frequencies for

the less

common allele of the 6209T>C; 11482G>A; 13041A>G and 14995A>T PLIN

polymorphisms were: 0.37; 0.24; 0.40 and 0.38, respectively. A strong

pairwise linkage

disequilibrium was observed between the PLIN 6209T>C and the PLIN 11482G>A

polymorphisms (D¢¥: 0.96; p<0.001). The PLIN 11482G>A polymorphism was the

only

one that was statistically associated with weight and BMI in the obese

patients. Table 1

shows anthropometric, biochemical, clinical and lifestyle characteristics

of the study

subjects according to the PLIN 11482G>A polymorphism. At baseline, we

observed that

carriers of the A allele had significantly less body weight and BMI than

GG homozygotes

(P<0.05). This association remained statistically significant even after

additional control

for potential confounders (smoking, drinking, physical activity,

education, type 2 diabetes

and menopausal status in women). Due to the high linkage disequilibrium

between the

PLIN 11482G>A and PLIN 6209T>C polymorphisms, lower mean body weight was

also

observed in carriers of the 6209 C allele; however the difference did not

reach the

statistical significance (P=0.071).

After baseline data were collected, weight reduction treatments were

prescribed

(Table 1). 42 patients received weight-loss medications combined with

diet, and 92

patients were prescribed to receive only an energy-restricted diet.

Patients assigned to the

energy-restricted diet, and who were not receiving medication for weight

loss, were

invited to participate in the one-year follow-up study. Forty-eight

patients (9 men and 39

women) were followed for the entire 1-year diet period and had complete

dataset at each

time point (at 3, 6 and 12 months). After the dietary intervention, we

found a statistically

significant (P=0.015) gene-diet interaction between the PLIN 11482G>A

polymorphism

in body weight decrease in response to diet. No statistically significant

interaction terms

were found for the other PLIN polymorphisms. Table 1 also shows baseline

characteristics of the 48 patients that completed the 1-year

energy-restricted follow-up

study according to the PLIN 11482G>A polymorphism. No statistically

significant

differences were observed in baseline variables between the two genotype

groups.

Smoking, drinking, education, physical activity, diabetes and menopausal

status in

women did not differ either. Interestingly, although both genotype groups

received the

same energy-restricted diet, weight loss differed significantly between

the two groups.

Figure 1 shows body weight means (gender and age adjusted) in the 48 obese

subjects

who completed the study for weight reduction under the energy-restricted

diet according

to the PLIN 11482G>A polymorphism. The intervention resulted in a

significant decrease

in mean body weight (from 114.3¡¾3.9 kg at baseline to 105.5¡¾3.5/ kg at

1-year; P-lineal

trend: 0.020) in patients with wild-type genotype (GG). Conversely,

patients with the

variant allele (A) did not show significant changes in mean body weight

(from 105.0¡¾4.6

kg at baseline to 104.3¡¾4.4 kg at 1-year; P-lineal trend: 0.985). The

difficulty in losing

weight among A allele-carriers was consistently observed at 3, 6 and 12

months, reducing

the likelihood that this finding was observed by chance. As baseline body

weight was

higher in GG subjects and to control for the potential influence of this

fact in the

observed interaction, we adjusted the statistical model for baseline BMI.

After the

adjustment for baseline BMI, the gene-diet interaction between the PLIN

11482G>A

polymorphism and the dietary intervention remained statistically

significant (P for

interaction= 0.035). Further adjustment of the model for education,

smoking, physical

activity, diabetes and menopausal status did not modify the statistical

significance of the

gene-diet interaction (P<0.05).

Moreover, as prevalence of diabetes was higher (although no statistically

significant) in carriers of the A allele, the potential modulation of

diabetes status in the

gene-diet interaction was also tested. We did not observe a statistically

significant

interaction term between the PLIN 11482G>A polymorphism, the low-energy

diet and

diabetes status in determining body weight (P=0.902). When the stratified

analysis of the

gene-diet interaction was carried out in non-diabetic and in diabetic

patients we observed

this homogeneity of the effect. In both non-diabetic and diabetic

subjects, body weight

decreased over the course of the intervention in subjects homozygous for

the PLIN

11482G allele (from 111.9¡¾4.5 kg at baseline to 103.4¡¾4.3/ kg at 1-year

in non-diabetic

patients; and from 125.3¡¾7.5 kg at baseline to 115.7¡¾6.4/ kg at 1-year

in diabetic

patients). However, in carriers of the variant allele (A) no decreases in

body weight were

observed. This gene-diet interaction effect was statistically significant

(P=0.041) in non-diabetic

subjects. In diabetic subjects, although the magnitude of the effect was

similar,

the interaction term did not reach the statistical significance due to

limitations in sample

size (P=0.203)

Finally, the allelic effect of the PLIN 11482G>A in determining

body-weight

response to the 1-year low-energy diet was tested in the whole sample.

Table 2 shows

adjusted means of body-weight at baseline, 3, 6 and 12 months and percent

of change

depending on the PLIN genotypes (GG, GA, AA). This gene-diet interaction

was

statistically significant (P=0.041) and showed that the A allele has a

¡°dominant¡± effect,

because no significant differences between GA and AA carriers in the

difficulty of losing

weight were observed.

DISCUSION

In the present study we have confirmed the role of the PLIN 11482G>A

polymorphism in determining body-weight in humans. In a previous

investigation,

carried out in subjects randomly selected from the general population in

the same

geographical area (14), we have reported that the PLIN 11482G>A

polymorphism was

significantly associated with body weight and obesity risk. Thus, the

11482A variant-allele

was associated with a lower obesity risk [Odds ratio (OR) = 0.56, 95% CI:

0.36-

0.89] in women. At baseline, in this morbidly obese population, the 11482A

variant allele

was associated with a much greater effect on body weight (~9%) than in the

general

population (~3.5%), suggesting a more prominent role of variations at the

PLIN locus in

morbidly obese subjects. The maximization of genetic effects of important

candidate

gene for obesity in severely obese subjects has been pointed out by Bell

et al (20) in their

recent review about the genetics of human obesity. Another interesting

contrast between

morbidly obese patients and the general population is that association was

only observed

in women from the general population (14), and we have shown similar

gender-specific

associations a White American (21) and Asian populations (22). Conversely,

in obese

patients, the PLIN 11482A variant allele was associated with lower

body-weight in both

men and women. The reason for this discrepancy is unknown; however, it is

likely that

the higher adiposity observed in severely obese men as compared with men

from the

general population largely contribute to this association. The evidence

from animal

models suggests similar effects in both male and female mice (12).

Therefore, more

human studies analyzing PLIN variation in men are needed to confirm if the

effect of

PLIN variation on anthropometric variables in men depends on the degree of

obesity.

In agreement with results from animal models (11, 12), the ¡°protective¡±

effects of

the PLIN 11482G>A minor allele observed in obese patients at baseline, as

well as in

women from the general population, are compatible with a reduced

expression of the

11482A-variant allele as compared with GG homozygotes. Data from animal

models

have consistently shown that targeted disruption of the perilipin gene

results in healthy

mice that are much leaner and more muscular than wild-type controls and

had increased

levels of basal lipolysis (11, 12). In support of this hypothesis, Kern et

al (13) in a study

carried out in 44 healthy subjects (5 men and 39 women), demonstrated a

significant

positive relationship between perilipin expression and obesity. Although

the PLIN

11482G>A polymorphism is located in an intron, and it does not appears to

be functional

according to traditional standards, Mottagui-Tabar et al (8) in a study

carried out in

human fat cells of obese women, have demonstrated that the perilipin

protein content was

markedly decreased and lypolisis increased in carriers of the

11482A-variant allele

supporting the observed results.

Despite the apparent ¡°protective¡± role of the 11482A-variant allele

associated

with lower body-weight at baseline, our dietary intervention follow-up

study has revealed

that carriers of this allele at the PLIN locus are more resistant to

weight loss in response

to an energy-restricted diet than GG homozygotes. Therefore, patients with

the 11482A

variant-allele did not show significant changes in mean body weight.

Conversely,

subjects homozygotes for the 11482G allele had a greater and statistically

significant

mean weight loss during the same 1-year low-energy diet. In addition it

seems that this

effect is ¡°dominant¡± because we have found the same difficulty in losing

weight in both

GA and AA patients. Although the PLIN 6209T>C paralleled the effect of the

PLIN

11482G>A SNP due to the high degree of linkage disequilibrium, a haplotype

analysis

(results not shown) indicated that the observed effect was mainly due to

the PLIN

11482G>A polymorphism. This is the first study on weight loss and PLIN

variation in

humans in response to a long-term energy-restricted diet and the molecular

mechanism to

explain the observed results remains to be explained. However, considering

the results

obtained in perilipin knockout mouse that are resistant to diet induced

obesity (17), we

can speculate that carriers of the 11482A-variant allele (associated with

less perilipin

expression) might experiment a ¡°buffer¡± effect by which body-weight

regulation in these

subjects is more independent of the energy intake than in GG homozygotes.

Another

aspect that remains to be investigated is macronutrient influence in the

PLIN-diet

interaction. In our study, the dietary target for fat content in the low

energy diet was

relatively high according to the typical Mediterranean diet, in which

olive oil is the main

fat consumed (23), and little is known about the ways in which

macronutrients or energy

restriction affect the regulation of adipose tissue gene expression (24).

In conclusion, our results show that the PLIN 11482G>A polymorphism may

predict outcome of body-weight reduction strategies based on low-energy

diets. rs

of the A allele might have higher stability in the mechanisms that control

body-weight

and a higher difficulty in losing weight in response to a low-energy diet.

This difficulty

was consistently observed at 3, 6 and 12 months, reducing the likelihood

that this finding

was observed by chance However, because this is the first longitudinal

investigation,

there is a need to confirm the present findings in other interventional

studies.

Table 2. Effects of the PLIN 11482G>A polymorphism on weight loss during

the energy-restricted diet depending on the genotype. Gender and

age-adjusted means

........................................

---GG (n=33) GA (n=9) AA (n=6)

---Mean (SE) % change* Mean (SE) % change* Mean (SE) % change*

........................................

Baseline 114.3 (3.9) 0 106.3 (6.5) 0 102.9 (6.7) 0

3-Months 108.8 (5.1) -4.8 106.7 (8.7) 0.37 101.9 (8.9) -0.97

6-Monts 106.9 (3.8) -6.6 106.7 (6.4) 0.37 102.8 (6.7) -0.09

1-Year 105.5 (3.5) -7.7 105.9 (6.1) -0.38 101.9 (6.3) -0.97

----P**: 0.864 P**: 0.898 P**: 0.020

.......................................

*: Percent of change (percent of increase or percent of decrease) was

calculated as: (baseline bodyweight minus body weight at each

time-period)*100 / baseline body weight.

**P: P value for lineal trend in the multivariate gender and age-adjusted

models for repeated measures depending on the PLIN 11482G>A genotypes (GG,

GA or AA). Further adjustment for smoking, drinking, education, diabetes

and baseline BMI did not modify the statistical significance of results.

Al Pater, PhD; email: old542000@...

____________________________________________________

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