Insulin Signals Through the Dorsal Vagal Complex to Regulate Energy Balance

Abstract

Insulin signaling in the hypothalamus regulates food intake and hepatic glucose production in rodents. Although it is known that insulin also activates insulin receptor in the dorsal vagal complex (DVC) to lower glucose production through an extracellular signal-related kinase 1/2 (Erk1/2)-dependent and phosphatidylinositol 3-kinase (PI3K)-independent pathway, it is unknown whether DVC insulin action regulates food intake. We report here that a single acute infusion of insulin into the DVC decreased food intake in healthy male rats. Chemical and molecular inhibition of Erk1/2 signaling in the DVC negated the acute anorectic effect of insulin in healthy rats, while DVC insulin acute infusion failed to lower food intake in high fat-fed rats. Finally, molecular disruption of Erk1/2 signaling in the DVC of healthy rats per se increased food intake and induced obesity over a period of 2 weeks, whereas a daily repeated acute DVC insulin infusion for 12 days conversely decreased food intake and body weight in healthy rats. In summary, insulin activates Erk1/2 signaling in the DVC to regulate energy balance.

Glucagon action in the brain

“…The dorsal vagal complex (DVC), located in the brainstem, is another key brain site known to regulate several autonomic functions, including peripheral glucose and energy homeostasis, via neural and hormonal signals [21]. Indeed, studies have confirmed that insulin [22,23], glucagon-like peptide 1 (GLP-1) [24,25] and leptin [26] signalling in the DVC regulate glycaemia and/or feeding behaviour. In light of the fact that glucagon receptors are also abundantly expressed in the brainstem [1,27], and peripherally administered glucagon alters neuronal activity in the brainstem [28], it was plausible that, analogous to the MBH, glucagon could initiate a signalling cascade in the DVC to regulate peripheral metabolism.…”

Insulin action in the hypothalamus and dorsal vagal complex

“…Indeed, direct administration of insulin into the DVC lowers food intake as early as 90 min compared with DVC saline infusions (Filippi et al . ). The mechanism underlying DVC insulin‐induced satiety involves the activation of DVC Erk1/2, because molecular and chemical inhibition of Erk1/2 signalling negates the ability of DVC insulin infusion to reduce feed et al .ing.…”

“…Furthermore, direct inhibition of DVC Erk1/2 per se induces obesity (Filippi et al . ), while DVC leucine sensing activates Erk1/2 to lower feeding (Blouet & Schwartz, ).…”

“…Nonetheless, rats fed with a high‐fat diet fail to lower food intake following a DVC insulin infusion (Filippi et al . ), while hypothalamic insulin infusion fails to suppress appetite in diet‐induced obese rodents (Clegg et al . ), in association with impaired Akt activation and dysregulated pro‐opiomelanocortin (Clegg et al .…”

Inhibition of Mitochondrial Fission and iNOS in the Dorsal Vagal Complex Protects from Overeating and Weight Gain

“…Intracerebroventricular (ICV) injection of insulin in the mediobasal hypothalamus (MBH) decreased hepatic glucose production (HGP) (Obici et al, 2002b;Pocai et al, 2005), while selective decrease in insulin receptor levels in the hypothalamus resulted in hyperphagia and increased fat mass (Obici et al, 2002a). In rodents, the dorsal vagal complex (DVC) of the brain is another important regulator of glucose metabolism (Filippi et al, 2012) and food intake (Filippi et al, 2014). In particular, the nucleus of the solitary tract (NTS) in the DVC senses insulin and triggers a neuronal relay to decrease HGP and food intake (Filippi et al, 2012;Filippi et al, 2014).…”