Gut-derived GIP activates central Rap1 to impair neural leptin sensitivity during overnutrition

Abstract

Nutrient excess, a major driver of obesity, diminishes hypothalamic responses to exogenously administered leptin, a critical hormone of energy balance. Here, we aimed to identify a physiological signal that arises from excess caloric intake and negatively controls hypothalamic leptin action. We found that deficiency of the gastric inhibitory polypeptide receptor ( Gipr ) for the gut-derived incretin hormone GIP protected against diet-induced neural leptin resistance. Furthermore, a centrally administered antibody that neutralizes GIPR had remarkable antiobesity effects in diet-induced obese mice, including reduced body weight and adiposity, and a decreased hypothalamic level of SOCS3, an inhibitor of leptin actions. In contrast, centrally administered GIP diminished hypothalamic sensitivity to leptin and increased hypothalamic levels of Socs3 . Finally, we show that GIP increased the active form of the small GTPase Rap1 in the brain and that its activation was required for the central actions of GIP. Altogether, our results identify GIPR/Rap1 signaling in the brain as a molecular pathway linking overnutrition to the control of neural leptin actions.

Antiobesogenic effects of central GIPR antagonism

“…GLP-1 infusions, but not GIP alone or GIP-GLP-1 combination infusions, lower energy intake compared with that achieved with saline infusion controls. Rather, coinfusion of GIP and GLP-1 negates the appetite-suppressing effects of GLP-1 (24), which may support the findings of Kaneko et al (15). Nonetheless, comparing and contrasting the food intake-regulatory effects of CNS versus peripheral GIPR signaling in rodents, nonhuman primates, and humans in obese, diabetic, and healthy conditions, as well as dissecting the time-dependent effects of GIPR inhibition and/or activation (Figure 1) should remain a priority in obesity research.…”

“…Notably, the work presented by Kaneko and colleagues shows that GIPR antagonism prevents HFD-induced increases in Rap1 activation (15). Support for the hypothesis that EPAC/Rap1 signaling is necessary for hypothalamic GIPR signaling to induce leptin resistance and obesity was obtained in mice with Rap1 deficiency in forebrain structures including hypothalamic nuclei (Rap1 ΔCNS ).…”

“…An integral connection exists between hypothalamic leptin and insulin action, defects of which predispose to obesity and type 2 diabetes; and it remains to be seen whether CNS GIP signaling also affects CNS insulin sensitivity. Furthermore, given that CNS leptin and insulin action are involved not only in energy bal-inhibition blocked leptin action, indicating that EPAC mediates GIP/GIPR signaling to inhibit hypothalamic leptin action (15). Furthermore, applying GIP (both in vivo and ex vivo) increased the active form of the small GTPase Rap1, a direct target of EPAC.…”

“…Kaneko et al report that peripheral administration of exogenous GIP increases levels in the blood (mimicking the levels observed in obesity) as well as cerebrospinal fluid, suggesting that blood-brain GIP transport is related to the central actions of leptin on food intake and body weight regulation (15). Of note, the CNS effect of leptin on food intake and body weight in HFD-fed mice is only partially blocked by GIP; thus, central leptin resistance is not fully attributable to GIP and could have other sources.…”

“…In this issue of the JCI, Kaneko and colleagues (15) provide compelling evidence of a mechanism that drives weight reduction in response to inhibition of GIPR signaling within the brain ( Figure 1). The authors administered a previously characterized (16) neutralizing monoclonal antibody (Gipg013), which specifically and potently antagonizes GIPR, directly into the rodent brain.…”