Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons

Abstract

Summary Leptin plays a pivotal role in regulation of energy balance. Via unknown central pathways leptin also affects peripheral glucose homeostasis and locomotor activity. We hypothesized that specifically Pro-opiomelanocortin (POMC) neurons mediate those actions. To examine this possibility we applied Cre-Lox technology to express leptin receptors (ObRb) exclusively in POMC neurons of the morbidly obese, profoundly diabetic, and severely hypoactive leptin receptor deficient Leprdb/db mice. We here show that expression of ObRb only in POMC neurons leads to a marked decrease in energy intake and a modest reduction in body weight in Leprdb/db mice. Remarkably, blood glucose levels are entirely normalized. This normalization occurs independently of changes in food intake and body weight. In addition, physical activity is greatly increased despite profound obesity. Our results suggest that leptin signaling exclusively in POMC neurons is sufficient to stimulate locomotion and prevent diabetes in the severely hypoactive and hyperglycemic obese Leprdb/db mice.

Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice

“…ordinated glucose homeostasis (17,18). In addition, VMH neurons are important, as demonstrated by the fact that microinjections of leptin into the VMH of lean mice increase glucose uptake in the skeletal muscle, heart, and brown adipose tissue (45,46).…”

“…By chiefly acting on neurons within the CNS, leptin suppresses food intake and increases energy expenditure, and hence restrains excessive body weight gain (16). In addition, leptin directly governs glucose homeostasis, mainly by activating cognate leptin receptors (LEPRs) in neurons within the hypothalamic arcuate nucleus (ARH) (17)(18)(19)(20). Interestingly, leptin and insulin share similar intracellular signaling pathways in hypothalamic neurons, such as the PI3K signaling cascade (21,22).…”

“…Because of the established importance of the CNS in mediating the glycemia-lowering actions of leptin in the context of either a high (17)(18)(19)(20) or low (27)(28)(29) circulating insulin level, we hypothesized that leptin's antidiabetic effects could also be mediated by brain neurons in the context of T1D. To test this hypothesis directly, we assessed the metabolic outcomes of CNSrestricted leptin administration in a mouse model of T1D.…”

Characterization of murine melanocortin receptors mediating adipocyte lipolysis and examination of signalling pathways involved

“…Furthermore, loss of MC4R function is the most frequent monogenetic alteration in severely obese humans (Krude et al 1998) and in severe, early onset childhood obesity the frequency of mutations in the MC4R locus is 4-6% (Farooqi et al 2003). Besides the effect on satiety and energy expenditure, the melanocortin system is believed to influence insulin release and insulin sensitivity (Fan et al 2000;Huo et al 2009). The melanocortin peptides and their receptors are also suspected to have a direct lipolytic effect on adipose tissues in rodents (Cho et al 2005;Boston 1999;Spirovski et al 1975).…”

Functional human antibody CDR fusions as long-acting therapeutic endocrine agonists

“…It is known that leptin functions by activating leptin receptors located in the central nervous system and peripheral tissues (45,46). We therefore analyzed whether hLeptin-CDR3H-coil-Herceptin up-regulated gene expression in liver and hypothalamus at multiple time points by quantitative PCR in mice treated with the fusion protein ( Table 2).…”