Transgenic MSH overexpression attenuates the metabolic effects of a high-fat diet.
To determine whether long-term melanocortinergic activation can attenuate the metabolic effects of a high fat diet, mice overexpressing an NH(2)-terminal POMC transgene that includes alpha- and gamma(3)-MSH were studied on either a 10% low-fat diet (LFD) or 45% high-fat diet (HFD). Weight gain was modestly reduced in transgenic (Tg-MSH) male and female mice vs. wild type (WT) on HFD (P < 0.05) but not LFD. Substantial reductions in body fat percentage were found in both male and female Tg-MSH mice on LFD (P < 0.05) and were more pronounced on HFD (P < 0.001). These changes occurred in the absence of significant feeding differences in most groups, consistent with effects of Tg-MSH on energy expenditure and partitioning. This is supported by indirect calorimetry studies demonstrating higher resting oxygen consumption and lower RQ in Tg-MSH mice on the HFD. Tg-MSH mice had lower fasting insulin levels and improved glucose tolerance on both diets. Histological and biochemical analyses revealed that hepatic fat accumulation was markedly reduced in Tg-MSH mice on the HFD. Tg-MSH also attenuated the increase in corticosterone induced by the HFD. Higher levels of Agrp mRNA, which might counteract effects of the transgene, were measured in Tg-MSH mice on LFD (P = 0.02) but not HFD. These data show that long-term melanocortin activation reduces body weight, adiposity, and hepatic fat accumulation and improves glucose metabolism, particularly in the setting of diet-induced obesity. Our results suggest that long-term melanocortinergic activation could serve as a potential strategy for the treatment of obesity and its deleterious metabolic consequences.
Lee
Michelle
M
Department of Medicine, Columbia University College of Physicians and Surgeons, 630 West 168th St., New York, NY 10032, USA.
Kim
Andrea
A
Chua
Streamson C
SC
Obici
Silvana
S
Wardlaw
Sharon L
SL
D000818:Animals; D001823:Body Composition / Q000235:genetics; D001835:Body Weight / Q000235:genetics; D004036:Diet, Atherogenic; D004435:Eating / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis / Q000235:genetics; D008055:Lipids / Q000032:analysis; D008099:Liver / Q000033:anatomy & histology / Q000737:chemistry; D008297:Male; D009074:Melanocyte-Stimulating Hormones / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009765:Obesity / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D009929:Organ Size / Q000235:genetics; D010101:Oxygen Consumption / Q000235:genetics; D012129:Respiratory Function Tests
D008055:Lipids; D009074:Melanocyte-Stimulating Hormones; D005947:Glucose