Abstract
Hypothalamic neurons respond to nutritional cues by altering gene expression and neuronal excitability. The mechanisms that control such adaptive processes remain unclear. Here we define populations of POMC neurons in mice that are activated or inhibited by insulin and thereby repress or inhibit hepatic glucose production (HGP). The proportion of POMC neurons activated by insulin was dependent on the regulation of insulin receptor signaling by the phosphatase TCPTP, which is increased by fasting, degraded after feeding and elevated in diet-induced obesity. TCPTP-deficiency enhanced insulin signaling and the proportion of POMC neurons activated by insulin to repress HGP. Elevated TCPTP in POMC neurons in obesity and/or after fasting repressed insulin signaling, the activation of POMC neurons by insulin and the insulin-induced and POMC-mediated repression of HGP. Our findings define a molecular mechanism for integrating POMC neural responses with feeding to control glucose metabolism.
Highlights
Insulin acts on peripheral tissues including liver, muscle and adipose tissue to directly control glucose metabolism, while acting in the brain to concordantly regulate nutrient fluxes, feeding behaviour and energy homeostasis (Varela and Horvath, 2012)
Taken together these results are consistent with deficiencies in T-cell protein tyrosine phosphatase (TCPTP) promoting insulin receptor (IR) signaling to increase the proportion of POMC neurons that are activated by insulin to drive the melanocortin-dependent improvement in glucose metabolism
In this study we demonstrate that POMC neurons can be either inhibited or activated by insulin and that the balance of excitation versus inhibition is dictated by the phosphatase TCPTP
Summary
Insulin acts on peripheral tissues including liver, muscle and adipose tissue to directly control glucose metabolism, while acting in the brain to concordantly regulate nutrient fluxes, feeding behaviour and energy homeostasis (Varela and Horvath, 2012). The contributions of the IR in controlling feeding and energy expenditure are best understood in the arcuate nucleus (ARC) of the hypothalamus, a specialized brain region comprising of neurons proximal to the fenestrated capillaries of the median eminence This position allows ARC neurons to respond to peripheral circulating factors such as leptin and insulin that convey information on the nutritional and metabolic status of the organism. Leptin hyperpolarizes and inhibits NPY/AgRP neurons and represses Npy/Agrp expression acting via several pathways, including the Janus-activated kinase (JAK)À2/signal transducer and activator of transcription (STAT)À3 pathway and the PI3K/AKT pathway (Cowley et al, 2001; Elias et al, 1999; van den Top et al, 2004; Varela and Horvath, 2012; Zhang et al, 2015) In this way leptin and insulin act to alleviate the inhibitory constraints on POMC neurons and the melanocortin response. Our studies define a mechanism for linking POMC neuronal plasticity with the nutritional and metabolic state of the organism
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