Phenotypic and genetic variation in leptin as determinants of weight regain.
OBJECTIVE
Over 75% of obese subjects fail to maintain their weight following weight loss interventions. We aimed to identify phenotypic and genetic markers associated with weight maintenance/regain following a dietary intervention.


METHODS
In the 2-year Dietary Intervention Randomized Controlled Trial, we assessed potential predictors for weight changes during the 'weight loss phase' (0-6 months) and the 'weight maintenance/regain phase' (7-24 months). Genetic variation between study participants was studied using single-nucleotide polymorphisms in the leptin gene (LEP).


RESULTS
Mean weight reduction was -5.5% after 6 months, with a mean weight regain of 1.2% of baseline weight during the subsequent 7-24 months. In a multivariate regression model, higher baseline high-molecular-weight adiponectin was the only biomarker predictor of greater success in 0- to 6-month weight loss (β = -0.222, P-value = 0.044). In a multivariate regression model adjusted for 6-month changes in weight and various biomarkers, 6-month plasma leptin reduction exhibited the strongest positive association with 6-month weight loss (β = 0.505, P-value < 0.001). Conversely, 6-month plasma leptin reduction independently predicted weight regain during the following 18 months (β = -0.131, P-value < 0.013). Weight regain was higher among participants who had a greater (top tertiles) 6-month decrease in both weight and leptin (+3.4% (95% confidence interval 2.1-4.8)) as compared with those in the lowest combined tertiles (+0.2% (95% confidence interval -1.1 to 1.4)); P-value < 0.001. Weight regain was further significantly and independently associated with genetic variations in LEP (P = 0.006 for both rs4731426 and rs2071045). Adding genetic data to the phenotypic multivariate model increased its predictive value for weight regain by 34%.


CONCLUSIONS
Although greater reduction in leptin concentrations during the initial phase of a dietary intervention is associated with greater weight loss in the short term, plasma leptin reduction, combined with the degree of initial weight loss and with genetic variations in the LEP gene, constitutes a significant predictor of subsequent long-term weight regain.
Obesity Clinic, Meuhedet Health Services, Jerusalem, Israel.
G
G
Erez
Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.|Talpiot Medical Leadership Program, Chaim Sheba Medical Center, Tel-Hashomer, Israel.
A
A
Tirosh
The S. Daniel Abraham Center for Health and Nutrition, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
A
A
Rudich
Department of Human Genetics, Hadassah-University Hospital, Jerusalem, Israel.
V
V
Meiner
Nuclear Research Center Negev, Dimona, Israel.
D
D
Schwarzfuchs
Unit of Epidemiology, Hebrew University-Hadassah School of Public Health, Jerusalem, Israel.
N
N
Sharon
Center for Research, Prevention and Treatment of Atherosclerosis, Hadassah-University Hospital, Jerusalem, Israel.
S
S
Shpitzen
Department of Medicine, University of Leipzig, Leipzig, Germany.
M
M
Blüher
Department of Medicine, University of Leipzig, Leipzig, Germany.
M
M
Stumvoll
Institute of Laboratory Medicine, University of Leipzig, Leipzig, Germany.
J
J
Thiery
Institute of Laboratory Medicine, University of Leipzig, Leipzig, Germany.
G M
GM
Fiedler
Unit of Epidemiology, Hebrew University-Hadassah School of Public Health, Jerusalem, Israel.
Y
Y
Friedlander
Center for Research, Prevention and Treatment of Atherosclerosis, Hadassah-University Hospital, Jerusalem, Israel.
E
E
Leiterstdorf
The S. Daniel Abraham Center for Health and Nutrition, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
I
I
Shai
D015415:Biomarkers / Q000378:metabolism; D015992:Body Mass Index; D004038:Diet, Reducing / Q000379:methods; D005260:Female; D014644:Genetic Variation; D006801:Humans; D020738:Leptin / Q000097:blood / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D015430:Weight Gain / Q000235:genetics* / Q000502:physiology
D015415:Biomarkers; D020738:Leptin