Objective

The steep rise in the prevalence of obesity and its related metabolic syndrome have become a major worldwide health concerns. Melanocortin peptides from hypothalamic arcuate nucleus (Arc) POMC neurons induce satiety to limit food intake. Consequently, Arc Pomc-deficient mice (ArcPomc^−/−) exhibit hyperphagia and obesity. Previous studies demonstrated that the circulating levels of adiponectin, a protein abundantly produced and secreted by fat cells, negatively correlate with obesity in both rodents and humans. However, we found that ArcPomc^−/− mice have increased circulating adiponectin levels despite obesity. Therefore, we investigated the physiological function and underlying mechanisms of hypothalamic POMC in regulating systemic adiponectin levels.

Methods

Circulating adiponectin was measured in obese ArcPomc^−/− mice at ages 4–52 weeks. To determine whether increased adiponectin was a direct result of ArcPomc deficiency or a secondary effect of obesity, we examined plasma adiponectin levels in calorie-restricted mice with or without a history of obesity and in ArcPomc^−/− mice before and after genetic restoration of Pomc expression in the hypothalamus. To delineate the mechanisms causing increased adiponectin in ArcPomc^−/− mice, we determined sympathetic outflow to adipose tissue by assessing epinephrine, norepinephrine, and tyrosine hydroxylase protein levels and measured the circulating adiponectin in the mice after acute norepinephrine or propranolol treatments. In addition, adiponectin mRNA and protein levels were measured in discrete adipose tissue depots to ascertain which fat depots contributed the most to the high level of adiponectin in the ArcPomc^−/− mice. Finally, we generated compound Adiopoq^−/−:ArcPomc^−/− mice and compared their growth, body composition, and glucose homeostasis to the individual knockout mouse strains and their wild-type controls.

Results

Obese ArcPomc^−/− female mice had unexpectedly increased plasma adiponectin compared to wild-type siblings at all ages greater than 8 weeks. Despite chronic calorie restriction to achieve normal body weights, higher adiponectin levels persisted in the ArcPomc^−/− female mice. Genetic restoration of Pomc expression in the Arc or acute treatment of the ArcPomc^−/− female mice with melanotan II reduced adiponectin levels to control littermate values. The ArcPomc^−/− mice had defective thermogenesis and decreased epinephrine, norepinephrine, and tyrosine hydroxylase protein levels in their fat pads, indicating reduced sympathetic outflow to adipose tissue. Injections of norepinephrine into the ArcPomc^−/− female mice reduced circulating adiponectin levels, whereas injections of propranolol significantly increased adiponectin levels. Despite the beneficial effects of adiponectin on metabolism, the deletion of adiponectin alleles in the ArcPomc^−/− mice did not exacerbate their metabolic abnormalities.

Conclusion

In summary, to the best of our knowledge, this study provides the first evidence that despite obesity, the ArcPomc^−/− mouse model has high circulating adiponectin levels, which demonstrated that increased fat mass is not necessarily correlated with hypoadiponectinemia. Our investigation also found a previously unknown physiological pathway connecting POMC neurons via the sympathetic nervous system to circulating adiponectin, thereby shedding light on the biological regulation of adiponectin.

中文翻译：

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尽管肥胖，但下丘脑 POMC 缺乏会增加循环脂联素。

客观的

肥胖及其相关代谢综合征的患病率急剧上升，已成为全球主要的健康问题。来自下丘脑弓状核 (Arc) POMC 神经元的黑皮质素肽诱导饱腹感以限制食物摄入。因此，Arc Pomc 缺陷小鼠（Arc Pomc ^-/-）表现出食欲过盛和肥胖。先前的研究表明，脂联素（一种由脂肪细胞大量产生和分泌的蛋白质）的循环水平与啮齿动物和人类的肥胖呈负相关。然而，我们发现 Arc Pomc ^-/-尽管肥胖，小鼠的循环脂联素水平增加。因此，我们研究了下丘脑 POMC 在调节全身脂联素水平方面的生理功能和潜在机制。

方法

在 4-52 周龄的肥胖 Arc Pomc ^-/-小鼠中测量循环脂联素。为了确定增加的脂联素是 Arc Pomc缺乏的直接结果还是肥胖的继发效应，我们检查了有或没有肥胖病史的卡路里限制小鼠以及基因恢复前后Arc Pomc ^-/-小鼠的血浆脂联素水平的POMC下丘脑表达。描述导致 Arc Pomc 中脂联素增加的机制^-/-对于小鼠，我们通过评估肾上腺素、去甲肾上腺素和酪氨酸羟化酶蛋白水平确定了脂肪组织的交感神经流出量，并在急性去甲肾上腺素或普萘洛尔治疗后测量了小鼠体内的循环脂联素。此外，在离散的脂肪组织库中测量脂联素 mRNA 和蛋白质水平，以确定哪些脂肪库对 Arc Pomc ^-/-小鼠中高水平的脂联素贡献最大。最后，我们生成了复合Adiopoq ^-/- :Arc Pomc ^-/-小鼠，并将它们的生长、身体成分和葡萄糖稳态与单个基因敲除小鼠品系及其野生型对照进行了比较。

结果

与野生型同胞相比，肥胖的 Arc Pomc ^-/-雌性小鼠在超过 8 周的所有年龄具有意外增加的血浆脂联素。尽管为了达到正常体重而进行慢性卡路里限制，但 Arc Pomc ^-/-雌性小鼠中仍存在较高的脂联素水平。Arc中Pomc表达的遗传恢复或用melanotan II对Arc Pomc ^-/-雌性小鼠进行急性治疗会降低脂联素水平以控制同窝仔猪值。Arc Pomc ^-/-小鼠的产热有缺陷，脂肪垫中的肾上腺素、去甲肾上腺素和酪氨酸羟化酶蛋白水平降低，表明脂肪组织的交感神经外流减少。向 Arc Pomc ^-/-雌性小鼠注射去甲肾上腺素降低了循环脂联素水平，而注射普萘洛尔则显着增加了脂联素水平。尽管脂联素对代谢有益，但 Arc Pomc ^-/-小鼠中脂联素等位基因的缺失并未加剧其代谢异常。

结论

总之，据我们所知，这项研究提供了第一个证据，即尽管肥胖，Arc Pomc ^-/-小鼠模型具有高循环脂联素水平，这表明增加的脂肪量不一定与低脂联素血症相关。我们的研究还发现了一种以前未知的生理途径，通过交感神经系统将 POMC 神经元连接到循环脂联素，从而阐明脂联素的生物调节。