Leptin enhances hypothalamic lactate dehydrogenase A (LDHA)-dependent glucose sensing to lower glucose production in high-fat-fed rats.

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 remains elusive. Here, we first report that short-term high-fat feeding disrupts 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 LDHA-dependent glucose sensing in the hypothalamus to lower glucose production in high-fat-fed rodents in vivo.

Glucagon action in the brain.

In recent years, novel discoveries have reshaped our understanding of the biology of brain glucagon in the regulation of peripheral homeostasis. Here we compare and contrast brain glucagon action in feeding vs glucose regulation and depict the physiological relevance of brain glucagon by reviewing their actions in two key regions of the central nervous system: the mediobasal hypothalamus and the dorsal vagal complex. These novel findings pave the way to future therapeutic strategies aimed at enhancing brain glucagon action for the treatment of diabetes and obesity. This review summarises a presentation given at the 'Novel data on glucagon' symposium at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by Young Lee and colleagues, DOI: 10.1007/s00125-016-3965-9 ), and by Russell Miller and Morris Birnbaum, DOI: 10.1007/s00125-016-3955-y ) and an overview by the Session Chair, Isabel Valverde (DOI: 10.1007/s00125-016-3946-z ).

A fatty acid-dependent hypothalamic-DVC neurocircuitry that regulates hepatic secretion of triglyceride-rich lipoproteins.

The brain emerges as a regulator of hepatic triglyceride-rich very-low-density lipoproteins (VLDL-TG). The neurocircuitry involved as well as the ability of fatty acids to trigger a neuronal network to regulate VLDL-TG remain unknown. Here we demonstrate that infusion of oleic acid into the mediobasal hypothalamus (MBH) activates a MBH PKC-δ→KATP-channel signalling axis to suppress VLDL-TG secretion in rats. Both NMDA receptor-mediated transmissions in the dorsal vagal complex (DVC) and hepatic innervation are required for lowering VLDL-TG, illustrating a MBH-DVC-hepatic vagal neurocircuitry that mediates MBH fatty acid sensing. High-fat diet (HFD)-feeding elevates plasma TG and VLDL-TG secretion and abolishes MBH oleic acid sensing to lower VLDL-TG. Importantly, HFD-induced dysregulation is restored with direct activation of either MBH PKC-δ or KATP-channels via the hepatic vagus. Thus, targeting a fatty acid sensing-dependent hypothalamic-DVC neurocircuitry may have therapeutic potential to lower hepatic VLDL-TG and restore lipid homeostasis in obesity and diabetes.

Insulin action in the hypothalamus and dorsal vagal complex.

Insulin resistance is a hallmark feature of type 2 diabetes and obesity. In addition to the classical view that insulin resistance in the liver, muscle and fat disrupts glucose homeostasis, studies in the past decade have illustrated that insulin resistance in the hypothalamus dysregulates hepatic glucose production and food intake, leading to type 2 diabetes and obesity. This invited review argues that in addition to the hypothalamus, insulin signalling in the dorsal vagal complex regulates hepatic glucose production and food intake. A thorough understanding of the physiological and pathophysiological mechanisms of insulin action in the hypothalamus and dorsal vagal complex is necessary in order to identify therapeutic targets for obesity and type 2 diabetes.

Glucagon and lipid signaling in the hypothalamus.

Hyperglycemia, caused in part by elevated hepatic glucose production (GP), is a hallmark feature of diabetes and obesity. The hypothalamus responds to hormones and nutrients to regulate hepatic GP and glucose homeostasis. This invited perspective focuses on the molecular signaling and biochemical pathways involved in the gluco-regulatory action of hypothalamic glucagon signaling and lipid sensing in health and disease. Recent evidence generated via genetic, molecular and chemical experimental approaches indicates that glucagon and lipid signaling independently trigger complementary hypothalamic mechanisms to lower GP. Thus, targeting hypothalamic glucagon or lipid signaling may have therapeutic potential in diabetes and obesity.

Hypothalamic glucagon signaling inhibits hepatic glucose production.

Glucagon activates hepatic protein kinase A (PKA) to increase glucose production, but the gluco-stimulatory effect is transient even in the presence of continuous intravenous glucagon infusion. Continuous intravenous infusion of insulin, however, inhibits glucose production through its sustained actions in both the liver and the mediobasal hypothalamus (MBH). In a pancreatic clamp setting, MBH infusion with glucagon activated MBH PKA and inhibited hepatic glucose production (HGP) in rats, as did central glucagon infusion in mice. Inhibition of glucagon receptor-PKA signaling in the MBH and hepatic vagotomy each negated the effect of MBH glucagon in rats, whereas the central effect of glucagon was diminished in glucagon receptor knockout mice. A sustained rise in plasma glucagon concentrations transiently increased HGP, and this transiency was abolished in rats with negated MBH glucagon action. In a nonclamp setting, MBH glucagon infusion improved glucose tolerance, and inhibition of glucagon receptor-PKA signaling in the MBH enhanced the ability of intravenous glucagon injection to increase plasma glucose concentrations. We also detected a similar enhancement of glucose concentrations that was associated with a disruption in MBH glucagon signaling in rats fed a high-fat diet. We show that hypothalamic glucagon signaling inhibits HGP and suggest that hypothalamic glucagon resistance contributes to hyperglycemia in diabetes and obesity.