Post-Developmental Adipocyte Autophagy in Control of Insulin-Glucose Homeostasis

University Of Utah, Salt Lake City UT

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Abstract

Summary /Abstract Obesity, Metabolic Syndrome, and Type 2 diabetes are characterized by insulin resistance affecting multiple tissues (e.g., liver, muscle, and fat). Recent studies determined that intracellular autophagy plays an important role maintaining the metabolic health of tissues involved in the pathogenesis of insulin resistance. Autophagy is the intracellular lysosomal trafficking pathway that maintains energy homeostasis and counteracts multiple forms of cellular stress. In addition, autophagy is the sole mechanism for mitochondrial degradation and turnover in cells. Autophagy functions in skeletal muscle, liver, pancreatic beta cells, and hypothalamus to maintain insulin-glucose homeostasis; in addition, autophagy is required for lipolysis in liver. Prior studies examining the role of autophagy in adipose tissue utilized mouse models in which adipocyte autophagy was impaired during embryogenesis. These mice were lean and protected from diet-induced obesity, and exhibited enhanced insulin sensitivity and glucose intolerance. Such observations led to speculations that inhibiting autophagy in adipocytes might provide a promising strategy for treating or preventing obesity and its metabolic consequences. However, despite their apparently favorable metabolic phenotype, the mice with embryonic impairment of autophagy were not healthy: they exhibit increased rates of death (40% at 12 weeks of age) and inflammation and macrophage infiltration in adipose tissue. Due to the extreme alterations of adipocyte development and adipose tissue depot formation in these mice, they are not adequate models for assessing the post-developmental role of autophagy in the mature adipocyte. We hypothesize autophagy plays an important, protective function in mature adipocytes, and post-developmental impairment of adipocyte autophagy will induce intracellular stress and insulin-resistance via established signaling mechanisms; in addition, we predict autophagic stress will cause release of unique circulating factors from adipocytes that drive systemic insulin-resistance and glucose intolerance via direct effects on other organs (e.g., liver, muscle, and pancreatic beta cells). The Overall Objectives of this project are: (i) to determine the role of adipocyte autophagy in the pathogenesis of insulin-resistance and glucose intolerance in vivo by defining specific target tissues and molecular actions through which adipocyte autophagy regulates systemic metabolism in the adult; and (ii) to define the normal regulation and metabolic functions of autophagy in mature adipocytes, independently of the role of autophagy in adipocyte development/differentiation. We genetically engineered mice so that autophagy can be turned off in adulthood, after the developmental period of intense adipogenesis, via a tamoxifen- inducible genetic impairment. Preliminary findings with mature adipocyte autophagy knockout mice indicate autophagy does not regulate adiposity but is necessary for healthy insulin-glucose homeostasis. In the proposed work we will extend these observations to a systematic assessment of the tissue specific-mechanisms through which impairment of autophagy in mature adipocytes causes insulin resistance and glucose intolerance in mice in vivo (Aim #1); and we will make use of cultured primary adipocyte progenitor cells to study how the timing of autophagy impairment during adipogenesis influences the metabolic phenotype of adipocytes in vitro (Aim #2).