Chronic High-Fat Diet Exacerbates Sexually Dimorphic Pomc(tm1/tm1) Mouse Obesity

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.