Multiple pathways operate in the brain to maintain a balanced anabolic and catabolic effect, thus keeping body weight constant. The NPY/AgRP pathway facilitates orexigenic actions with resultant anabolic effects and weight gain, while the MSH/CART pathway antagonises this effect with anorexigenic action facilitating weight loss. Peripherally initiated signals from the adipose tissue and  gut are transmitted to the forebrain areas (which include hypothalamic arcuate nucleus)  and the hindbrain areas (nucleus of tractus solitarius)  respectively. Front Neuroendocrinol. 2002 Jan;23(1):2-40

Insulin, like Leptin, circulates in blood in proportion to the fat mass.  Nutr Rev. 2002 Oct;60(10 Pt 2):S20-9   Insulin is evolving as a central regulator of, or signal for satiety induction. Insulin receptors have been demonstrated in the arcuate nucleus.    Insulin inhibits NPY/AgRP neurones while stimulating POMC neurones. Nature. 2000 Apr 6;404(6778):661-71   Central insulin administration increases hypothalamic POMC mRNA content. ICV insulin administration suppresses food intake, an effect that is blocked by melanocortin receptor antagonists. Insulin injection into hypothalamic ventromedial and paraventricular nuclei increases body temperature Brain Res. 1991 Aug 2;555(2):193-201   while decreasing food intake, Physiol Behav. 1992 Apr;51(4):753-66    the former possibly being mediated through increased fatty acid oxidation by increased sympathetic outflow to the brown adipose tissues (BAT). In keeping with this latter effect, insulin administration peripherally increases plasma catecholamine levels.  Circulation. 1997 Dec 2;96(11):4104-13.

Infusing insulin into the third cerebroventricle decreases hepatic glucose production without a demonstrable effect on circulating insulin levels. Nat Med. 2002 Dec;8(12):1376-82.   On the other hand, administration into the third ventricle of insulin specific antibodies or anti sense oligonucleotides directed against the insulin receptor results in increased hepatic glucose production (reduced hepatic sensitivity to circulating insulin).  Nat Neurosci. 2002 Jun;5(6):566-72. Thus insulin may modulate hepatic glucose metabolism through its central effects. Signal transduction of the insulin in the CNS still requires the same pathways as in the periphery, namely the IRS -PI3K-PKB pathway, as PI3K inhibitors block the effects of centrally administered insulin. Diabetes. 2003 Feb;52(2):227-31.   But in contrast to IRS-1 in the periphery, it may be IRS-2 that mediates insulin's action in the CNS. In keeping with this is the finding that IRS-1 is not concentrated in ventral hypothalamic nuclei while IRS-2 is abundantly found in the arcuate nucleus.  Am J Physiol Endocrinol Metab. 2003 Jul;285(1)   Also IRS-1 deficient mice do not show abnormal energy balance, while IRS-2 knock out results in increased food intake and body fat.  J Clin Invest. 2004 Oct;114(7):908-16. In fact, insulin administration centrally produces hypothalamic PI3K activation in cells of the mediobasal hypothalamus which contain IRS-2. Further, intracerebroventricular insulin adminstration produces serine phosphorylation of hypothalamic Protein kinase B which is a major downstream mediator of PI3K signalling.

The role of glucose transporters in the CNS is not clear. GLUT-4 receptors that facilitate glucose uptake by insulin in muscles, is also present in the lateral hypothalamus, Neuroscience. 2002;111(1):19-34.   albeit in lower concentrations that elsewhere in the brain. While the role of GLUT 4 receptors in insulin signalling is far from clear, GLUT-8 receptors which have been localised particularly in the hypothalamus, J Biol Chem. 2000 Feb 18;275(7):4607-12.   may help in effecting the central actions of insulin. Glucose administration peripherally results in translocation of this receptor from the intracellular location to the plasma membrane, Comp Neurol. 2002 Oct 14;452(2):103-14.   and this effect seems to be brought about by insulin. The majority of NPY neurones  express glucokinase, the "glucose sensor" molecule in the pancreas,  Diabetes. 2000 May;49(5):693-700.    which may perform similar function in the CNS as well.

Antagonising the effect of insulin in the hypothalamus could thus potentially have deleterious effects on satiety induction and hepatic glucose metabolism. SOCS3 or Suppressor of Cytokine Signalling is a protein in the JAK-STAT (Janus Kinase-STAT) pathway which is activated by leptin binding to its receptor, which then inhibits leptin signalling through inactivation of the leptin receptor and JAK-2, preventing activation of STAT-3.  Induction of Suppressor of Cytokine Signalling (SOCS3), terminates insulin signalling by modification of the insulin receptor and IRS proteins and could produce hypothalamic resistance to the actions of insulin, producing hyperphagia, obesity and glucose intolerance.

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    This page was last updated on: 07/03/2007

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