Chronic High-Fat Diet Exacerbates Sexually Dimorphic Pomctm1/tm1 Mouse Obesity

Abstract

Mice with a targeted mutation in the pro-opiomelanocortin ( Pomc ) gene ( Pomc tm1/tm1 mice) are unable to synthesize desacetyl- α -MSH and α -MSH and they develop obesity when fed chow diet. In this study, we hypothesized that a chronic high-fat (HF) diet exacerbates Pomc tm1/tm1 mouse obesity. Male and female Pomc wt/wt and Pomc tm1/tm1 mice were fed low-fat (LF) (10 kcal percent fat) or HF (45 kcal percent fat) diets from weaning for 23 weeks. We show that Pomc tm1/tm1 mouse obesity is sexually dimorphic and exacerbated by an HF diet. Male Pomc tm1/tm1 mice develop obesity because they are hyperphagic compared with Pomc wt/wt mice when fed an LF or HF diet. Female Pomc tm1/tm1 mice develop obesity when feeding on an LF or HF diet because they exhibit signs of reduced energy expenditure (no change in feed efficiency; body weight gained exceeding energy intake) compared with Pomc wt/wt mice. A chronic HF diet exacerbates male Pomc tm1/tm1 and Pomc wt/wt mouse obesity, and the increased energy intake fully accounts for increased weight gain. In contrast, female Pomc wt/wt mice are protected from chronic HF diet–induced obesity because they reduce the amount of HF diet eaten, and they appear to increase their energy expenditure (no change in feed efficiency but energy intake exceeding body weight gained). A chronic HF diet exacerbates female Pomc tm1/tm1 mouse obesity due to impaired ability to reduce the amount of HF diet eaten and apparent impaired HF diet–induced adaptive thermogenesis. Our data show that desacetyl- α -MSH and α -MSH are required for sexually dimorphic HF diet–induced C57BL/6J obesity. In conclusion, desacetyl- α -MSH and α -MSH play salutary roles in sexually dimorphic melanocortin obesity and sexually dimorphic HF diet–induced C57BL/6J obesity.

Hypothalamic C2-domain protein involved in MC4R trafficking and control of energy balance

“…Male C2CD5KO mice significantly consumed more food during light phase with no significant differences seen during dark phase (Figure 2M). Before BW diversion, female C2CD5KO mice consumed significantly more calories than WT mice (8 weeks of age) only when fed WD (Supplementary 1H) consistent with the BW data (showing no difference between WT and KO when fed NC) and with the hypothesis that hypothalamic C2CD5 may be involved in the exacerbation of sexually dimorphic obesity induced by chronic western-diet [39]. Thus, lack of C2CD5 causes hyperphagia in males when fed NC or WD and in females when fed WD.…”

Hypothalamic C2-domain protein involved in MC4R trafficking and control of energy balance

“…Before BW diversion, female C2CD5KO mice consumed significantly more calories than WT mice (8 weeks of age) only when fed WD (Supplementary 1H) consistent with the BW data (showing no difference between WT and KO if NC-fed). This finding also supports the hypothesis that hypothalamic C2CD5 may be involved in the exacerbation of sexually dimorphic obesity induced by chronic western-diet [39]. Thus, lack of C2CD5 causes hyperphagia in NC-and WD-fed male, and in WD-fed female mice.…”

“…Recent data shows the evidence of a sexual dimorphic nature of the brain in its response to high fat diet and in many cases, the use of chronic high fat diet exacerbates sexually dimorphic mouse obesity. Hubbard et al showed that hypothalamic MC4R ligands are required for observing sexual dimorphism [39]. More investigations will be necessary to evaluate whether gonadal hormones regulate hypothalamic C2CD5 and define such a sexual dimorphic mouse obesity.…”

EphrinB1 modulates glutamatergic inputs into POMC neurons and controls glucose homeostasis

“…Our findings also suggest sexual dimorphism in the melanocortin system, as the lack of Efnb2 in POMC neurons does not lead to impaired gluconeogenesis in females, but it does result in changes to refeeding after an overnight fast. The ARH has not been primarily viewed as a dimorphic structure, but recent studies showed differences between males and females in the number of ARH POMC neurons, their firing rate, the development of diet-induced obesity and the activation of STAT3 in POMC neurons (44–46).…”