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.
Highlights
Obesity is a common problem worldwide, as it contributes to type 2 diabetes and other life style-related diseases in susceptible people with genetic predispositions
Deletion of insulin receptor (IR) in the hypothalamus using an antisense oligonucleotide induced hyperphagia and insulin resistance [8]. These data consistently demonstrate that insulin in the central nervous system (CNS) stimulates insulin signaling in some hypothalamic cell types, thereby suppressing food intake and regulating glucose metabolism
We reported that one-day high fat diet (HFD) feeding induced S6 kinase (S6K) activation, downregulation of insulin receptor substrate (IRS)-1 tyrosine phosphorylation, and downregulation of Akt phosphorylation in the rat hypothalamus [46]
Summary
Obesity is a common problem worldwide, as it contributes to type 2 diabetes and other life style-related diseases in susceptible people with genetic predispositions. Exploring medications that are effective in treating obesity by suppressing food intake and/or enhancing energy expenditure is among the most important research goals in modern medicine. Targeting insulin in the brain could be a valid approach for treating obesity and type 2 diabetes, provided that its functions in the brain remain intact. These beneficial effects are severely disturbed by excessive nutrition, the consumption of fatty foods, and obesity itself, a condition referred to as brain insulin resistance. Clarifying the mechanism by which brain insulin resistance occurs, and devising strategies for breaking this vicious cycle, are important for developing new medications for the effective treatment of obesity and type 2 diabetes
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
