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

由于性别差异存在于代谢综合征的几乎所有方面， 仅使用男性受试者会导致不良、脱靶或简单无效结局的不成比例风险 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， 胚细胞生长因子21（FGF 21），一种由肝脏响应营养应激而产生的多肽激素， 是治疗代谢性疾病的有前景的靶点。在雄性动物中，以药理学剂量肌肉注射给药- 证明葡萄糖耐量，并通过增加交感神经流出到脂肪减少体重和体脂 组织，增加产热作用。因此，几家主要公司正在开发基于FGF 21的COM- 磅临床使用。然而，令人惊讶的是，对FGF 21在女性中的代谢作用知之甚少。我们 最近发表的初步数据有力地支持FGF 21作为一种关键机制， 对膳食蛋白质“稀释”性二态代谢反应--一种新的营养干预 在雄性小鼠、大鼠和人类中的体重减轻和改善的葡萄糖和脂质代谢。在这个项目中，我们计划 通过识别特定的神经内分泌和细胞自主机制， 其中FGF 21在雄性和雌性中引起不同的代谢反应。这其中最重要的假设是 有一种说法是，在雌激素受体β存在的情况下，下丘脑中的FGF 21信号传导增加了雌激素受体β的表达。 交感神经驱动男性脂肪组织，而不是女性，脂肪细胞中的FGF 21信号抑制了交感神经驱动男性脂肪组织，而脂肪细胞中的FGF 21信号抑制了交感神经驱动男性脂肪组织。 雌性对肾上腺素能刺激的分解代谢反应，但雄性无。我们将用药理学方法检验假设- 脑（Aim 1）和脂肪组织（Aim 2）中FGF 21信号传导的逻辑、遗传和营养操纵 雄性和雌性小鼠，连同间接量热法和同位素示踪剂辅助测量脂质 周转这些实验有望描绘神经内分泌和分子机制， 利用脂肪量的性二态调节，从而促进适当和有针对性的递送 肥胖和代谢疾病的营养和药物干预。鉴于 由于对FGF 21本身作为治疗靶点感兴趣，我们惊讶地注意到几乎对其一无所知， 对女性受试者的代谢影响。因此，这项工作不仅在生理上具有重要意义，而且还将 为基于FGF 21的治疗在男性和女性中的临床应用提供了新的见解。

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.