Central Ghrelin Signaling Mediates the Metabolic Response of C57BL/6 Male Mice to Chronic Social Defeat Stress

Abstract

Chronic stressors promote metabolic disturbances, including obesity and metabolic syndrome. Ghrelin, a peptide that promotes appetite and the accumulation of adipose tissue, is also secreted in response to stressors to protect the brain and peripheral tissues from the effects of these stressors. Here we demonstrate that elevated ghrelin levels produced by chronic exposure to social stress are associated with increased caloric intake and body weight gain in male C57BL mice. In contrast, stressed mice lacking ghrelin receptors (GHSR KO mice) or C57BL mice receiving chronic intracerebroventricular delivery of the ghrelin receptor antagonist [d-Lys(3)]-GHRP-6 show attenuated weight gain and feeding responses under the same social stress paradigm. Interestingly, stressed GHSR KO mice showed depleted sc and intrascapular brown fat depots, whereas stressed young wild-type mice did not. In old wild-type mice, chronic social defeat increased visceral and intrascapular brown fat depots in association with increases in obesity markers like hyperleptinemia and hyperinsulinemia along with increased hypothalamic expression of neuropeptide Y and Agouti related peptide. Importantly, the elevated expression of these peptides persisted least for 2 weeks after cessation of the stressor regimen. In contrast, old GHSR KO mice did not show these alterations after chronic social defeat. These results suggest that ghrelin plays an important role in the metabolic adaptations necessary to meet the energetic demands posed by stressors, but chronic exposure to stress-induced ghrelin elevations ultimately could lead to long lasting metabolic dysfunctions.

Chronic stress aggravates glucose intolerance in leptin receptor-deficient (db/db) mice

“…Similar to previously published data in strains not genetically predisposed to obesity (Patterson et al 2013;Sanghez et al 2013; Table 2), the current results further support the multistage and polygenic nature of T2D and suggest that the disease develops in the presence of multiple risk factors. In mouse strains of different genetic backgrounds, we and others showed that CSS aggravates diet-induced obesity and caused hypoactivity and hyperphagia (Table 2; Bartolomucci et al 2005Bartolomucci et al , 2009Dadomo et al 2011;Patterson et al 2013;Razzoli et al 2015a, b).…”

“…Finally, subordinate db/db mice showed a systemic lowgrade pro-inflammatory profile, as suggested by elevation of TNF-alpha levels and mild increase in IL-6 levels, in line with results in wild-type mice (Patterson et al 2013). Adipose tissue in obese and diabetic individuals might develop an inflammatory milieu which ultimately leads to insulin resistance (Patel et al 2013).…”

“…The observed glucose intolerance could thus be explained more as a stress-induced failure to suppress fasting-induced hepatic gluconeogenesis rather than impaired glucose clearance (Chan et al 1975). On the other hand, the dampened response of corticosterone to fasting of subordinate db/db mice apparently contrasts with the observed stress-induced elevation in corticosterone levels and hyperglycemia commonly induced by this model in different mouse strains (Sanghez et al 2013;Bartolomucci et al 2009;Patterson et al 2013). …”

“…In mouse strains of different genetic backgrounds, we and others showed that CSS aggravates diet-induced obesity and caused hypoactivity and hyperphagia (Table 2; Bartolomucci et al 2005Bartolomucci et al , 2009Dadomo et al 2011;Patterson et al 2013;Razzoli et al 2015a, b). In addition, stress in wild-type subordinate mice fed HFD caused a metabolic syndrome, glucose intolerance and insulin resistance; furthermore, they exhibit hormonal changes (i.e., higher leptin and decreased adiponectin) and excessive free fatty acids levels, both of which are recognized risk factors for the development of T2D.…”

“…Psychosocial stress is an important risk factor for to the development of diabetes, obesity and associated co-morbid disorders (Block et al 2009;Torres and Nowson 2007;Trento et al 2010). It can be modeled in mice using the chronic subordination stress (CSS) that induces vulnerability to obesity, metabolic syndrome and insulin resistance further aggravated by hypercaloric diet (e.g., Bartolomucci et al 2004Bartolomucci et al , 2009Dadomo et al 2011;Sanghez et al 2013;Razzoli et al 2014Razzoli et al , 2015aPatterson et al 2013). In this study, we aimed at establishing whether obese and diabetic prone db/db mice could develop an aggravated metabolic phenotype due to the exposure to the psychological challenge of CSS impinging upon their abnormal behavioral reactivity.…”