Department of Physiology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
Department of Anatomy and Medical Imaging, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
Endocrinology. 2019 May 1;160(5):1081-1096. doi: 10.1210/en.2018-00924.
Mice with a targeted mutation in the pro-opiomelanocortin (Pomc) gene (Pomctm1/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 Pomctm1/tm1 mouse obesity. Male and female Pomcwt/wt and Pomctm1/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 Pomctm1/tm1 mouse obesity is sexually dimorphic and exacerbated by an HF diet. Male Pomctm1/tm1 mice develop obesity because they are hyperphagic compared with Pomcwt/wt mice when fed an LF or HF diet. Female Pomctm1/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 Pomcwt/wt mice. A chronic HF diet exacerbates male Pomctm1/tm1 and Pomcwt/wt mouse obesity, and the increased energy intake fully accounts for increased weight gain. In contrast, female Pomcwt/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 Pomctm1/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.
携带靶向突变的 pro-opiomelanocortin（Pomc）基因（Pomctm1/tm1 小鼠）的小鼠无法合成去乙酰-α-MSH 和 α-MSH，并且在用常规饮食喂养时会发展为肥胖。在这项研究中，我们假设慢性高脂肪（HF）饮食会加剧 Pomctm1/tm1 小鼠肥胖。雄性和雌性 Pomcwt/wt 和 Pomctm1/tm1 小鼠从断奶开始分别喂食低脂肪（LF）（10%卡路里脂肪）或高脂肪（HF）（45%卡路里脂肪）饮食 23 周。我们表明，Pomctm1/tm1 小鼠肥胖具有性别二态性，并且 HF 饮食会加剧这种肥胖。雄性 Pomctm1/tm1 小鼠肥胖是因为与 Pomcwt/wt 小鼠相比，它们在喂食 LF 或 HF 饮食时表现出过度摄食。雌性 Pomctm1/tm1 小鼠肥胖是因为与 Pomcwt/wt 小鼠相比，它们在喂食 LF 或 HF 饮食时表现出能量消耗减少的迹象（饲料效率没有变化；体重增加超过能量摄入）。慢性 HF 饮食加剧了雄性 Pomctm1/tm1 和 Pomcwt/wt 小鼠肥胖，而增加的能量摄入完全解释了体重增加。相比之下，雌性 Pomcwt/wt 小鼠免受慢性 HF 饮食诱导的肥胖，因为它们减少了 HF 饮食的摄入量，并且似乎增加了能量消耗（饲料效率没有变化，但能量摄入超过体重增加）。慢性 HF 饮食加剧了雌性 Pomctm1/tm1 小鼠肥胖，因为它们减少 HF 饮食摄入量的能力受损，并且似乎 HF 饮食诱导的适应性产热受损。我们的数据表明，去乙酰-α-MSH 和 α-MSH 是 C57BL/6J 肥胖的性别二态性 HF 饮食诱导所必需的。总之，去乙酰-α-MSH 和 α-MSH 在性别二态性黑皮质素肥胖和性别二态性 HF 饮食诱导的 C57BL/6J 肥胖中发挥有益作用。
