State-dependent central synaptic regulation by GLP-1 is essential for energy homeostasis.

Central nervous system (CNS) control of metabolism plays a pivotal role in maintaining energy homeostasis. Glucagon-like peptide-1 (GLP-1, encoded by Gcg), secreted by a distinct population of neurons located within the nucleus tractus solitarius (NTS), suppresses feeding through projections to multiple brain targets1-3. Although GLP-1 analogs are proven clinically effective in treating type 2 diabetes and obesity4, the mechanisms of GLP-1 action within the brain remain unclear. Here, we investigate the involvement of GLP-1 receptor (GLP-1R) mediated signaling in a descending circuit formed by GLP-1R neurons in the paraventricular hypothalamic nucleus (PVNGLP-1R) that project to dorsal vagal complex (DVC) neurons of the brain stem in mice. PVNGLP- 1R→DVC synapses release glutamate that is augmented by GLP-1 via a presynaptic mechanism. Chemogenetic activation of PVNGLP-1R→DVC neurons suppresses feeding. The PVNGLP-1R→DVC synaptic transmission is dynamically regulated by energy states. In a state of energy deficit, synaptic strength is weaker but is more profoundly augmented by GLP-1R signaling compared to an energy-replete state. In an obese state, the dynamic synaptic strength changes in the PVNGLP-1R→DVC descending circuit are disrupted. Blocking PVNGLP-1R→DVC synaptic release or ablation of GLP-1R in the presynaptic compartment increases food intake and causes obesity, elevated blood glucose, and impaired insulin sensitivity. These findings suggest that the state-dependent synaptic plasticity in this PVNGLP-1R→DVC descending circuit mediated by GLP-1R signaling is an essential regulator of energy homeostasis.

ß-Cell Insulin Resistance Plays a Causal Role in Fat-Induced ß-Cell Dysfunction In Vitro and In Vivo.

In the classical insulin target tissues of liver, muscle, and adipose tissue, chronically elevated levels of free fatty acids (FFA) impair insulin signaling. Insulin signaling molecules are also present in ß-cells where they play a role in ß-cell function. Therefore, inhibition of the insulin/insulin-like growth factor 1 pathway may be involved in fat-induced ß-cell dysfunction. To address the role of ß-cell insulin resistance in FFA-induced ß-cell dysfunction we co-infused bisperoxovanadate (BPV) with oleate or olive oil for 48 hours in rats. BPV, a tyrosine phosphatase inhibitor, acts as an insulin mimetic and is devoid of any antioxidant effect that could prevent ß-cell dysfunction, unlike most insulin sensitizers. Following fat infusion, rats either underwent hyperglycemic clamps for assessment of ß-cell function in vivo or islets were isolated for ex vivo assessment of glucose-stimulated insulin secretion (GSIS). We also incubated islets with oleate or palmitate and BPV for in vitro assessment of GSIS and Akt (protein kinase B) phosphorylation. Next, mice with ß-cell specific deletion of PTEN (phosphatase and tensin homolog; negative regulator of insulin signaling) and littermate controls were infused with oleate for 48 hours, followed by hyperglycemic clamps or ex vivo evaluation of GSIS. In rat experiments, BPV protected against fat-induced impairment of ß-cell function in vivo, ex vivo, and in vitro. In mice, ß-cell specific deletion of PTEN protected against oleate-induced ß-cell dysfunction in vivo and ex vivo. These data support the hypothesis that ß-cell insulin resistance plays a causal role in FFA-induced ß-cell dysfunction.