Obesity and associated metabolic diseases are increasingly becoming a global health problem and new treatment approaches are of significant interest. The recent discovery of thermogenic adipose in humans and the finding that white adipose depots in humans and mice can be induced to upregulate brown-like characteristics (aka beige adipose) has revived interest in the possibility that triggering thermogenesis could significantly affect energy balance in humans and combat obesity. -arrestins are important regulators of -adrenergic signaling, as they are known to bind to activated receptors and cause desensitization by directing their ubiquitination and/or endosomal recycling. However, the classic and well-described -arrestins belong to a larger arrestin superfamily of proteins, grouped based on their predicted structural similarity. A subgroup of this family, termed alpha-arrestins, include thioredoxin interacting protein (Txnip) and five other proteins, termed arresti domain-containing proteins 1-5. Very little is known of the function of the alpha-arrestins, however studies in yeast have shown alpha-arrestins to function in coordinating receptor endocytosis, ubiquitination, and downstream signaling. It was hypothesized that alpha- arrestins' function overlaps with the -arrestins, however, recent studies on the alpha-arrestin Arrdc3 have shown it to function downstream from -arrestin, with a role in the trafficking of endocytosed 2-adrenergic receptor. These data posit a role for Arrdc3 as an adaptor protein between receptor targets and endosomal machinery. My sponsor's laboratory has recently identified one of the alpha-arrestins, Arrdc3, as a new regulator of obesity through the combination of human linkage data, human expression data, and mouse knockout studies. Specifically, Arrdc3 knockout (KO) mice are resistant to age-induced weight gain, have increased energy expenditure and have increased expression of thermogenic genes. Finally, adipose tissue isolated from Arrdc3 KO mice have increased responsiveness to -adrenergic stimulation. Using mice with adipocyte-specific knockout of Arrdc3, I will test whether brown and white adipocyte Arrdc3 regulates energy expenditure and thermogenesis and whether it contributes significantly to the obesity- resistant phenotype observed in the total knockout mice. Additionally, using cells in culture, I will test whether Arrdc3 regulates -adrenergic signaling n adipocytes. The insights from the proposed research will result in a better understanding of the role of Arrdc3, as well as the control of energy homeostasis and thermogenesis.
The treatment of obesity using agents to increase energy expenditure are currently of intense interest. However, an understanding of the mechanisms of energy homeostasis remains incomplete. The proposed research uses rigorous approaches to elucidate the recently identified role of the alpha-arrestin Arrdc3 in the regulation of energy homeostasis, beta-adrenergic signaling and obesity.
