The novel role of FGF21 in mediating sex-dependent responses to dietary macronutrients

由于代谢综合征的几乎所有方面都存在性别差异，治疗方法应运而生 只使用男性受试者会导致不成比例的不良结果、偏离目标或根本无效的风险。 在女性患者中。然而，绝大多数临床前生物医学研究只关注男性。纤维蛋白- 成纤维细胞生长因子21(FGF21)是肝脏在应对营养压力时产生的一种多肽激素， 是治疗代谢性疾病的一个很有前途的靶点。在男性中，按药理剂量注射- 改善糖耐量，通过增加交感神经向脂肪的流出来减轻体重和体脂 组织，增加产热。因此，几家大公司正在开发基于FGF21的COM- 临床使用的英镑。然而，令人惊讶的是，人们对FGF21在女性体内的代谢作用知之甚少。我们的 最近公布和初步的数据有力地支持了FGF21作为促进 对食物蛋白质“稀释”的性二型代谢反应--一种新的营养干预方法 减轻体重，改善雄性小鼠、大鼠和人类的糖脂代谢。在这个项目中，我们计划 为了解决下一个关键步骤，通过以下方式确定特定的神经内分泌和细胞自主机制 FGF21在男性和女性中引起不同的代谢反应。其中最重要的假设是 有观点认为，在雌激素受体-β存在的情况下，下丘脑中的FGF21信号会增加 交感神经驱动男性而不是女性的脂肪组织，脂肪细胞中的FGF21信号抑制 女性对肾上腺素能刺激的分解代谢反应，而男性不是。我们将用药物来检验假说- 大脑(目标1)和脂肪组织(目标2)中FGF21信号的逻辑、遗传和营养调控 雄性和雌性小鼠，以及间接量热法和同位素示踪剂辅助的脂质测量 营业额。这些实验有望阐明神经内分泌和分子机制。 倾向于对脂肪团进行性二态调节，从而促进适当和有针对性的交付 肥胖症和代谢性疾病的营养和药物干预。鉴于相当大的 对于FGF21本身作为治疗靶点的兴趣，我们惊讶地注意到，对其几乎一无所知 女性受试者的代谢影响。因此，这项工作不仅在生理上很重要，而且还将 为基于FGF21的疗法在男性和女性中的临床应用提供新的见解。

Because sex differences exist in almost all aspects of the metabolic syndrome, treatments developed using only male subjects elicit a disproportionate risk for adverse, off-target, or simply ineffective outcomes among female patients. Yet the vast majority of pre-clinical biomedical research focuses only on males. Fibro- blast growth factor 21 (FGF21), a polypeptide hormone produced by the liver in response to nutritional stress, is a promising target for treatment of metabolic disease. In males, administration at pharmacologic doses im- proves glucose tolerance, and reduces body weight and body fat by increasing sympathetic outflow to adipose tissue, increasing thermogenesis. Consequently, several major companies are developing FGF21-based com- pounds for clinical use. Yet surprisingly little is known about the metabolic actions of FGF21 in females. Our recently published and preliminary data strongly support that FGF21 functions as a key mechanism facilitating the sexually dimorphic metabolic response to dietary protein ‘dilution’—a novel nutritional intervention eliciting weight loss and improved glucose and lipid metabolism in male mice, rats and humans. In this project, we plan to address the next critical step, by identifying specific neuroendocrine and cell-autonomous mechanisms by which FGF21 elicits divergent metabolic responses in males and females. The overarching hypothesis in this proposal is that, in the presence of estrogen receptor-beta, FGF21 signaling in the hypothalamus increases the sympathetic drive to adipose tissue in males but not females, and FGF21 signaling in the adipocyte inhibits the catabolic response to adrenergic stimulation in females but not males. We will test hypothesis using pharmaco- logic, genetic and nutritional manipulations of FGF21 signaling in the brain (Aim 1) and adipose tissue (Aim 2) of male and female mice, together with indirect calorimetry, and isotopic tracer-assisted measurements of lipid turnover. These experiments are expected to delineate neuroendocrine and molecular mechanisms contrib- uting to the sexually dimorphic regulation of fat mass, thereby facilitating the appropriate and targeted delivery of nutritional and pharmacological interventions in obesity and metabolic disease. In light of the considerable interest in FGF21 itself as a therapeutic target, we are surprised to note that almost nothing is known about its metabolic effects in female subjects. Therefore, this work is not only physiologically important, but it will also provide new insights in the clinical application of FGF21-based therapeutics in both men and women.