Restoring Leptin Signaling in Key Neurons Normalizes Metabolism
JAX® NOTES Issue 514, Summer 2009
The hormone leptin, first identified 15 years ago, is known for its ability to curb appetite and facilitate weight loss. Derived from fat cells, it regulates energy balance by activating the long form of the leptin receptor (ObRb). Mice that are either leptin- or leptin receptor-deficient become morbidly obese, hyperphagic, severely hyperglycemic, insulin resistant, and markedly sluggish. Studies have suggested that a small set of brain neurons, the hypothalamic, anorexigenic pro-opiomelanocortin (POMC) neurons, which express ObRbs, influence insulin sensitivity and glucose homeostasis, though the extent of this influence remains largely unknown. Additionally, an, as of yet, unspecified group of hypothalamic neurons controls voluntary movement and locomotor activity via leptin. To determine the role of POMC neurons in mediating leptin's pivotal roles in regulating energy balance, peripheral glucose homeostasis, and locomotor activity, a research team from Beth Israel Deaconess Medical Center, Harvard Medical School, and Baylor College of Medicine used Cre-Lox technology to selectively express ObRb only in the POMC neurons of leptin receptor-deficient, obese, hypoactive and diabetic mice, the BKS.Cg-Dock7m +/+ Leprdb/J (db/db; 000642) strain. These conditional mutant mice showed decreased food consumption, modestly reduced body weight, and greatly increased physical activity, despite profound obesity. Interestingly, the ObRb expression in the POMC neurons of db/db mice normalized their blood glucose levels and the mice did not become diabetic. These results suggest that drugs designed to restore leptin signaling in POMC neurons might have similar effects in people with severe type 2 diabetes and obesity (Huo et al. 2009).
Reference
Huo L, Gamber K, Greeley S, Silva J, Huntoon N, Leng XH, Bjorbaed C. 2009. Leptin-dependent control of glucose balance and locomotor activity by POMC neurons. Cell Metabolism 9:537-47.
