Sexually dimorphic metabolic responses mediated by CRF2 receptor during nutritional stress in mice

Abstract

BackgroundChronic stress is a major contributor in the development of metabolic syndrome and associated diseases, such as diabetes. High-fat diet (HFD) and sex are known modifiers of metabolic parameters. Peptide hormones corticotropin-releasing factor (CRF) and urocortins (UCN) mediate stress responses via activation and feedback to the hypothalamic-pituitary-adrenal (HPA) axis. UCN3 is a marker of pancreatic β-cell differentiation, and UCN2 is known to ameliorate glucose levels in mice rendered diabetic with HFD. CRF receptor 2 (CRF2) is the only known cognate receptor for UCN2/3. Here, we ascertained the role of CRF2 in glucose clearance, insulin sensitivity, and other parameters associated with metabolic syndrome in a mouse model of nutritional stress.MethodsWild-type (WT) and Crhr2−/− (null) mice of both sexes were fed either normal chow diet or HFD. After 8 weeks, blood glucose levels in response to glucose and insulin challenge were determined. Change in body and fat mass, plasma insulin, and lipid profile were assessed. Histological evaluation of liver sections was performed.ResultsHere, we show that genotype (Crhr2), sex, and diet were all independent variables in the regulation of blood glucose levels, body and fat mass gain/redistribution, and insulin resistance. Surprisingly, CRF2-deficient mice (Crhr2−/−) male mice showed similarly impaired glucose clearance on HFD and chow. HFD-fed female Crhr2−/− mice redistributed their fat depots that were distinct from wild-type females and male mice on either diet. Blood cholesterol and low-density lipoprotein (LDL) levels were elevated significantly in male Crhr2−/− mice; female Crhr2−/− mice were protected. Male, but not female Crhr2−/− mice developed peripheral insulin resistance. HFD, but not chow-fed wild-type male mice developed hepatic macrovesicular steatosis. In contrast, livers of Crhr2−/− male mice showed microvesicular steatosis on either diet, whereas livers of female mice on this 8-week HFD regimen did not develop steatosis.ConclusionsCRF2 receptor dysregulation is a sexually dimorphic risk factor in development of pre-diabetic and metabolic symptoms.Electronic supplementary materialThe online version of this article (10.1186/s13293-018-0208-4) contains supplementary material, which is available to authorized users.

Modeling Diet‐Induced Metabolic Syndrome in Rodents

“…[ 45 ] In the study by Paruthiyil et al., after HFD (60% kcal from fat) feeding for 8 weeks, only males had hyperinsulinemia and altered lipid profile. [ 48 ] This hyperinsulinemia presented only in male mice was also observed by Wu et al. after 14 weeks of exposure to an HFD 45% kcal from fat.…”

“…[45] In the study by Paruthiyil et al, after HFD (60% kcal from fat) feeding for 8 weeks, only males had hyperinsulinemia and altered lipid profile. [48] This hyperinsulinemia presented only in male mice was also observed by Wu et al after 14 weeks of exposure to an HFD 45% kcal from fat. [49] This convergent observation regarding insulin homeostasis is important in the context of this study since insulin resistance is one of the diagnostic criteria for the MetS.…”

Plasma Corticotropin-Releasing Factor Receptors and B7-2+ Extracellular Vesicles in Blood Correlate with Irritable Bowel Syndrome Disease Severity

“…CRF 1 activation initiates HPA responses and anxiety-like behavior, whereas CRF 2 activation brings systems back to homeostasis, and mediates anxiolytic behavior [11,12]. We have shown that CRF 2 plays a vital role in mediating metabolic [13] and immune responses [14,15,16,17,18,19]. CRF 2 receptor dysfunction is known to exacerbate edema, necrosis, and delayed healing [14,20].…”

Gonadal white adipose tissue-derived exosomal MiR-222 promotes obesity-associated insulin resistance

“…The high-fat diet-induced obese mice are commonly used as a model of insulin resistance. As noted in previous studies, the male mice were more severely affected by the high-fat diet (HFD) than the female mice [ 46 – 48 ]. In our study, we found that both the male and female HFD-fed mice exhibit insulin resistance and impaired glucose tolerance, but the impairments are worse in the male mice compared to the female mice.…”