Molecular Mechanisms of Hypothalamic Insulin Resistance

Abstract

Insulin exists in the central nervous system, where it executes two important functions in the hypothalamus: the suppression of food intake and the improvement of glucose metabolism. Recent studies have shown that both are exerted robustly in rodents and humans. If intact, these functions exert beneficial effects on obesity and diabetes, respectively. Disruption of both occurs due to a condition known as hypothalamic insulin resistance, which is caused by obesity and the overconsumption of saturated fat. An enormous volume of literature addresses the molecular mechanisms of hypothalamic insulin resistance. IKKβ and JNK are major players in the inflammation pathway, which is activated by saturated fatty acids that induce hypothalamic insulin resistance. Two major tyrosine phosphatases, PTP-1B and TCPTP, are upregulated in chronic overeating. They dephosphorylate the insulin receptor and insulin receptor substrate proteins, resulting in hypothalamic insulin resistance. Prolonged hyperinsulinemia with excessive nutrition activates the mTOR/S6 kinase pathway, thereby enhancing IRS-1 serine phosphorylation to induce hypothalamic insulin resistance. Other mechanisms associated with this condition include hypothalamic gliosis and disturbed insulin transport into the central nervous system. Unveiling the precise molecular mechanisms involved in hypothalamic insulin resistance is important for developing new ways of treating obesity and type 2 diabetes.

Keywords: food intake; glucose metabolism; hypothalamus; inflammation; insulin resistance; obesity.

Figure 1

Molecular mechanisms of insulin functions and associated modifications in the hypothalamus. Insulin enters the hypothalamus and suppresses food intake and hepatic glucose production. Many molecules disturb hypothalamic insulin signaling at several sites in response to saturated fatty acids (SFA), inflammation, and excess nutrition. Hypothalamic insulin also affects metabolic processes in white adipose tissue (WAT) and brown adipose tissue (BAT). The dot line shows a pathway less confirmed, and the dot line with “?” is a hypothetical unconfirmed pathway.