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.

Fig. 1

Intracellular signaling by the leptin (LepRb - cyan) and insulin receptor (magenta). Leptin binding to its receptor exhibits simple kinetic properties suggesting that one molecule of leptin binds to the leptin receptor (left side). Leptin binding to the extracellular domain of LepRb dimer induces JAK2 tyrosine kinases, which are noncovalently associated proximally with the receptor, to autophosphorylate (Heldin, 1995; Ihle et al., 1994; Myers et al., 2008). Activated Jak2 subsequently phosphorylates a number of substrates including the tyrosine residues (Y985, 1077, and Y1138) on the intracellular domain of the leptin receptor. STAT3 is recruited via its SH2 (src homology) domain to the distal tyrosine residue (Y1138) and is then phosphorylated by JAK2 (Banks et al., 2000; Bates et al., 2003; White et al., 1997). STAT3 subsequently dimerizes and translocates to the nucleus to modify the transcription of several genes including SOCS3 (Banks et al., 2000; Bjorbaek et al., 1998). SOCS3 is a negative regulator of cytokine signaling and acts as a negative regulator of leptin in a feedback loop (Bjorbaek et al., 1998). SOCS3 inhibits phosphorylation of the proximal tyrosine residue (Y985) on the leptin receptor and to a lesser degree on tyrosine residue (Y1077) (Bjorbak et al., 2000; Eyckerman et al., 2000). SOCS3 can also inhibit JAK2 and STAT3 directly (Dunn et al., 2005; Sasaki et al., 2000; Sasaki et al., 1999). In addition to providing a binding site for SOCS3, the proximal tyrosine residue (Y985) also binds SHP2 upstream of the ERK/MAPK pathway (Bahrenberg et al., 2002; Banks et al., 2000; Bjorbak et al., 2000; Kloek et al., 2002). PTP-1B is largely associated with the surface of the ER and negatively regulates leptin signaling by dephosphorylating JAK2 (Zabolotny et al., 2002). JAK2 activates the IRS-PI3K pathway which has been shown to alter gene transcription and modify cellular activity via activation of conductances such as the Katp and TRPC channels (Hill et al., 2008; Mirshamsi et al., 2004; Niswender et al., 2001; Qiu et al., 2010; Spanswick et al., 1997). Leptin also activates the mammalian target of rapamycin-ribosomal S6 kinase (mtor-S6K) pathway which are kinases known to regulate transcription and protein synthesis (Blouet et al., 2008; Cota et al., 2008; Cota et al., 2006). In contrast to leptin, insulin binding to its receptor exhibits complex kinetic properties suggesting that one molecule of insulin may bind and activate the insulin receptor, however another molecule of insulin may bind to a lower affinity binding site on the receptor as well (right side). Insulin binding to the extracellular alpha subunits of the insulin receptor induces autophosporylation of the intracellular beta subunits and is critical for insulin action in vivo (White et al., 1984; White et al., 1988). The insulin receptor has 8 tyrosine residues which can be phosphorylated (Ullrich et al., 1985). These sites exist in 3 clusters: juxtamembrane (Y960,Y950/972), tri-tyrosine (1146, 1150, 1151), and c-terminus (1316, 1322). The insulin receptor subsequently recruits and activates IRS proteins which in turn activate many of the same signaling cascades activated by leptin (cyan/magenta) including PI3K-AKT (Myers et al., 1992; Myers and White, 1993). The negative regulators of leptin receptor activity, SOCS3 and PTP1B, also feedback directly on the insulin receptor and inhibit signaling - both can also inhibit IRS1 directly (Elchebly et al., 1999; Emanuelli et al., 2001; Emanuelli et al., 2000; Goldstein et al., 2000; Kenner et al., 1996; Klaman et al., 2000). S6K also inhibits insulin signaling by phosphorylating IRS1 at multiple serine residues (Carlson et al., 2004; Harrington et al., 2004; Ozes et al., 2001; Tremblay et al., 2007).

Fig. 2

Effects of leptin receptor deletion in distributed hypothalamic neurons. The effects of direct leptin action in POMC (cyan), NPY/AgRP (magenta), or SF1 (grey) cells on energy and glucose homeostasis are revealed by selective deletion of leptin receptors. Mice lacking leptin receptors in POMC neurons alone exhibit decreased energy expenditure and locomotor activity resulting in increased adiposity and concomitant mild diabetes. Similarly, deletion of leptin receptors in SF1 neurons results in decreased energy expenditure resulting in increased adiposity. Finally, lack of leptin signaling in NPY/AgRP neurons results in mild obesity from decreased energy expenditure and locomotor activity; however glucose and insulin sensitivity was unaffected. Fig. modified from (Williams et al., 2009).