Leptin and insulin pathways in POMC and AgRP neurons that modulate energy balance and glucose homeostasis

Abstract

With the steady rise in the prevalence of obesity and its associated diseases, research aimed at understanding the mechanisms that regulate and control whole body energy homeostasis has gained new interest. Leptin and insulin, two anorectic hormones, have key roles in the regulation of body weight and energy homeostasis, as highlighted by the fact that several obese patients develop resistance to these hormones. Within the brain, the hypothalamic proopiomelanocortin and agouti-related protein neurons have been identified as major targets of leptin and insulin action. Many studies have attempted to discern the individual contributions of various components of the principal pathways that mediate the central effects of leptin and insulin. The aim of this review is to discuss the latest findings that might shed light on, and lead to a better understanding of, energy balance and glucose homeostasis. In addition, recently discovered targets and mechanisms that mediate hormonal action in the brain are highlighted.

Figure 1

Hypothalamic leptin and insulin signals regulate several peripheral functions. Leptin and insulin secreted by white adipose tissue (WAT) and the pancreas, respectively, inform the hypothalamus about the energy status of the organism. When LepR-b and InsR are activated by these hormones, they promote changes in hypothalamic neuropeptide expression, which cause alterations in peripheral functions to restore energy balance and glucose metabolism. Arc, arcuate nucleus; AgRP, agouti-related protein; InsR, insulin receptor; LepR-b, leptin receptor b; POMC, proopiomelanocortin; VMH, ventromedial hypothalamus.

Figure 2

Leptin and insulin signalling pathways in the Arc. Signal transducer and activator of transcription 3 (STAT3) is activated and phosphorylated when leptin binds to LepR-b. p-STAT3 binds to pomc and agrp promoters, stimulating pomc expression and inhibiting agrp. Leptin and insulin signalling pathways converge on PI3K. Activation of PI3K leads to phosphorylation and inactivation of FoxO1, a repressor of pomc expression. Phosporylation of FoxO1 provokes its nuclear export and allows STAT3 to bind to pomc and agrp promoters. It has been reported that inhibition of AMPK by leptin is mediated by mTOR [35]. AgRP, agouti-related protein; AKT, protein kinase B; AMPK, AMP-dependent kinase; FoxO1, Forkhead box protein O1; HIF, hypoxia-inducible factor; InsR, insulin receptor; IRS, insulin receptor substrate; JAK, Janus kinase; LepR-b, leptin receptor b; mTOR, mammalian target of rapamycin; PDK1, 3-phosphoinositide-dependent protein kinase 1; PI3K, phosphatidylinositol-3-kinase; POMC, proopiomelanocortin,; S6K,; STAT3, signal transducer and activator of transcription 3.

Figure 3

Autophagy in POMC and AgRP neurons. During starvation, when glucose levels are low, certain cytoplasmic organelles are sequestered in autophagosomes. In turn, these organelles are delivered into lysosomes, where they are broken into necessary nutrients to maintain cellular functions. AgRP, agouti-related protein; POMC, proopiomelanocortin.

Luis Varela

Tamas L Horvath