Adaptive metabolic flexibility and remodeling capacity of fat tissues is a feature essential to the maintenance of systemic metabolic homeostasis. The conditions of chronic nutrient overload lead to mitochondrial dysfunction, metabolic inflexibility, and systemic metabolic sequelae. Within this context, the PPARγ-FGF1 axis is a critical regulator of adipose remodeling and mediates adaptive changes to the metabolic program responding to both chronic metabolic stress as well as acute nutrient cues. To elucidate fat autonomous mechanisms of FGF1 in metabolic flexibility and tissue remodeling, I newly generated adipose-specific Fgf1 knockout (Fgf1 fat KO) mice.Upon high fat diet (HFD) stress, Fgf1 fat KO mice displayed a severe diabetic phenotype with atrophic visceral adipose tissue. Gross examination of Fgf1 fat KO visceral fat revealed atrophic and fibrotic alterations when placed on a HFD, indicative of a failure of adipose tissues to undergo proper adaptive remodeling. Consequently, Fgf1 fat KO mice had aggravated insulin resistance and hyperglycemia accompanied by severe hepatic steatosis when compared with control mice. Recent evidence suggests that the extensibility of mitochondria oxidative phosphorylation (OXPHOS) capacity critically supports the dynamic nature of adipose tissue physiology. In line with the idea, Fgf1 silenced adipocytes were found to have a profoundly decreased mitochondrial OXPHOS capacities in assays by extracellular flux analyzer. Mechanistically, Fgf1 silencing decreases cellular glycolytic capacity, which in turn results in a decrease in cellular pyruvate supply, resulting in OXPHOS decrease. Taken together, I propose that upregulation of adipose FGF1 triggered by HFD is required for proper adaptive remodeling of adipose tissues, and that the maladaptive phenotypes of FGF1 null adipose tissue is, in part, due to defective mitochondrial OXPHOS flexibility caused by a decrease in glycolytic capacity.
전신 대사 항상성 조절에 있어 지방조직의 유연한 성질은 필수적이다. 페록시좀증식체활성화 수용체 감마–산성섬유아세포성장인자축은 지방조직의 적응 과정에서 중요한 역할을 한다고 알려져 있지만, 정확한 기전은 밝혀져 있지 않다. 본 학위논문에서는 대사 조절에서 지방조직유래 산성섬유아세포성장인자의 역할을 밝히고자 한다.
