Leptin enhances hypothalamic LDHA-dependent glucose sensing to lower glucose production in high-fat fed rats. [Metabolism]
January 26th, 2018 by Mona A. Abraham, Mozhgan Rasti, Paige V. Bauer, Tony K.T. Lam
The responsiveness of glucose sensing per se to regulate whole-body glucose homeostasis is dependent on the ability of a rise in glucose to lower hepatic glucose production and increase peripheral glucose uptake in vivo. In both rodents and humans, glucose sensing is lost in diabetes and obesity but the site(s) of impairment remain elusive. We here first report that short-term high-fat feeding dirsupts hypothalamic glucose sensing to lower glucose production in rats. Second, leptin administration into the hypothalamus of high-fat fed rats restored hypothalamic glucose sensing to lower glucose production during a pancreatic (basal insulin)-euglycemic clamp and increased whole-body glucose tolerance during an intravenous glucose tolerance test. Finally, both chemical inhibition of hypothalamic lactate dehydrogenase (LDH) (achieved via hypothalamic LDH inhibitor oxamate infusion) and molecular knockdown of LDHA (achieved via hypothalamic lentiviral-LDHA shRNA injection) negated the ability of hypothalamic leptin infusion to enhance glucose sensing to lower glucose production in high-fat fed rats. In summary, our findings illustrate that leptin enhances LDH-A-dependent glucose sesning in the hypothalamus to lower glucose production in high-fat fed rodents in vivo.