Figure 4.

IRS phosphorylation in the hypothalamus: a potential mechanism for leptin's action on glycemia? a, Analysis of phospho-IRS1(Ser612) (left) and for phospho-IRS1(Ser307) (right) by immunohistochemistry in the ARC of Lep^ob/ob mice (n = 5–6 animals/group). phospho-IRS1-immunoreactive cells within the medial part of the ARC were counted in four region-matched representative sections of each animal. Fifteen minutes after either vehicle (aCSF) or leptin (4 μg) intracerebroventricular injection, animals were transcardially perfused. Data show means ± SEM. ***p < 0.001. b, Model proposing the central mechanism of sensitization of insulin signaling by leptin. In nonobese, leptin-sensitive animals, leptin might activate IRS1 to promote insulin action through the IRS1-PI3K pathway to regulate glucose homeostasis (left). During obesity, with the onset of leptin resistance, leptin might lose its ability to activate IRS1, resulting in a modification of this molecule to a lower affinity to insulin signal transduction (right). This will result in chronically impaired insulin signaling and the development of type 2 diabetes. LepR, Leptin receptor; IR, insulin receptor; JAK, Janus kinase.