Modulation of the central melanocortin system by leptin, insulin, and serotonin: Co-ordinated actions in a dispersed neuronal network

Abstract

Over the past century, prevalent models of energy and glucose homeostasis have been developed from a better understanding of the neural circuits underlying obesity and diabetes. From the early hypothalamic lesion reports to the more recent pharmacological and molecular/genetic studies, the hypothalamic melanocortin system has been shown to play a critical role in the regulation of metabolism. This review attempts to highlight contributions to our current understanding of how numerous neuromodulators (leptin, insulin, and serotonin) integrate with the central melanocortin system to coordinate alterations in energy and glucose balance.

PI3K signaling in the pathogenesis of obesity: The cause and the cure

“…There are several reports supporting the role of PI3Ks in the central effects of leptin action within the brain (Hill, Williams, 2008, Williams, Scott, 2011a, Williams, Sohn, 2011b. Leptin administration in the CNS increases Akt phosphorylation and other PI3K signaling intermediates, such as IRS-2, and the blockade of PI3K activation by i.c.v.…”

“…The melanocortin system mediates many of the feeding effect of both NPY/AgRP and POMC neurons in response to leptin/PI3K signaling (do Carmo et al , 2013, Seeley, Yagaloff, 1997, Williams, Scott, 2011a. In particular, the relevance of the α-MSHactivated melanocortin 4 receptor (MC4R) in energy homeostasis was first established by the obese phenotype of MC4R-knockout mice (Huszar et al , 1997).…”

“…We and others have previously focused on the relevance of the phosphatidylinositol 3-kinase (PI3K) signaling pathway in the pathogenesis of autoimmune and inflammatory diseases (Ghigo et al , 2010, Rommel et al , 2007, and recently an involvement of PI3Ks was found in regulation of central energy homeostasis (Plum et al , 2007, Williams et al , 2011a, Zhao et al , 2002. The use of specific as well as pan-PI3K inhibitors has M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 4 demonstrated that the activity of PI3K enzymes is important in autoimmune/inflammatory diseases as well as in the brain (Donato et al , 2010, Dudek et al , 1997, Ghigo, Damilano, 2010, Williams et al , 2011b.…”

Age-related alterations in the central thermoregulatory responsiveness to alpha-MSH

“…POMC neurons synthesize melanocortin agonist alpha-melanocyte-stimulatinghormone (alpha-MSH) (Williams et al, 2011;Xu et al, 2011).…”

Adipokines and their Involvement as a Target of New Drugs

“…M1 macrophages secrete pro-inflammatory cytokines such as TNF-α and IL-6, produce NO and reactive oxygen species (ROS), that contribute to obesity-related insulin resistance [26,27]. M2 macrophages produce IL-10, IL-1 receptor antagonist and arginase-1 and have been implicated in tissue remodeling [28], including clearance of dead or dying adipocytes and the recruitment and differentiation of adipocyte progenitors [29].…”