Neuronal Deletion of Ghrelin Receptor Attenuates Aging‐Associated Insulin Resistance and Cognitive Decline

Abstract

The aging process is characterized by a progressive decline of metabolic functions, insulin resistance, and cognitive impairment. We and others have reported that Growth Hormone Secretagogue Receptor (GHS‐R) plays a crucial role in metabolic regulation. GHS‐R is an endogenous G‐protein coupled receptor for the gut hormone ghrelin, and ghrelin signals the hypothalamus to increase feeding, decrease energy expenditure and reduce fat utilization. We previously reported that global GHS‐R deletion leads to a healthier metabolic profile compared to WT littermates in aging mice. We showed that ablation of GHS‐R ameliorates age‐associated metabolic impairments, reducing body weight/adiposity and improving insulin sensitivity during aging. Furthermore, we found that suppression of GHS‐R in neurons almost completely prevents diet‐induced obesity in mice (Syn1‐cre;Ghsrf/f), likely through increasing energy expenditure. Here, we further assessed metabolic and memory functions of 18–20 months‐old Syn1‐cre;Ghsrf/f and littermate Ghsrf/f control mice. Similar to young mice, old Syn1‐cre;Ghsrf/f mice showed reduced body weight and adiposity. Consistently, old Syn1‐cre;Ghsrf/f mice are more insulin sensitive than littermate controls. Interestingly, old Syn1‐cre;Ghsrf/f mice spent significantly more time exploring the novel object than the familiar object compared to controls in the novel object recognition test, at both 2 hours and 24 hours after training. These data suggest that old Syn1‐cre;Ghsrf/f mice retained short‐term and long‐term memory better than their littermate controls. In addition, old Syn1‐cre;Ghsrf/f mice exhibited significantly increased freezing behavior in both contextual and conditioned auditory stimulus tests in fear conditioning assay, indicating that old Syn1‐cre;Ghsrf/f mice retained better hippocampal‐dependent and amygdala‐dependent memory function compared to littermate controls. Overall, our data suggest that pan‐neuronal deletion of GHS‐R attenuates aging‐associated obesity, insulin resistance and memory impairment. The metabolic benefits derived from suppression of GHS‐R resemble the effects of calorie restriction, the most recognized strategy for increasing health span in multiple organisms. GHS‐R may provide a novel molecular target for improving metabolic fitness and cognitive function during aging.Support or Funding InformationWe gratefully acknowledges the support of NIH R56DK118334 (YS), NIA R01AG064869 (YS), and NIA R21AG061726 (CW).