Adipocytes secrete numerous lipid and protein factors with profound effects on systemic energy homeostasis. One such adipokine that we first identified in the early 1990's, adiponectin (previously referred to as Acrp30), has garnered significant attention as a potent mediator of insulin sensitivity and cell survival. Since that tim, a multitude of clinical reports and laboratory studies have repeatedly demonstrated decreased circulating levels of adiponectin in metabolic dysfunction, such as obesity and insulin resistance, in both humans and animal models. Mechanistically, adiponectin's effects on lipids, particularly the regulation of sphingolipid species, such as ceramides, are at the heart of a deeper understanding of its biological function. We would like to build upon our data that we have generated over the previous funding cycle. Center stage to this proposal is the analysis of tissue-specific effects of adiponectin receptors and their effects on cellular and systemic lipid levels, particularly sphingolipid levels, the impact of an acute loss of adiponectin function in th adult animal and a functional dissection of the contribution and heterogeneity of specific fat depots towards systemic adiponectin levels. Specifically, we would like to address these questions with the following Specific Aims: SA 1) To determine the consequences of adiponectin receptor overexpression in adipocytes and hepatocytes. As these receptors convey ceramidase activity upon a cell, we have a parallel set of mouse strains that allow us to overexpress acid ceramidase in target cells. With increasing evidence implicating caveolin-1 as a functional mediator, we will test the involvement of caveolin-1 on adiponectin receptor trafficking and enzymatic activity. SA 2) To define the consequences of an acute loss of adiponectin in adipocytes in the adult mouse. We will embark on a systemic analysis of adiponectin effects on lipids, including sphingolipids, in plasma and in critical target tissues asa function of dietary conditions and circulating adiponectin levels. SA 3) To elucidate the contributions of specific regional fat depots towards circulating adiponectin. Brown adipose tissue, in particular, is characterized by highly heterogeneous adiponectin expression. We will characterize these functionally distinct brown adipocytes. Combined, these studies will provide significant new insights into adipocyte secretory biology and the physiological effects of adiponectin, both locally, with respect to its effects on adipocytes, as well as systemically. The proposed lowering of ceramide levels within adipocytes and other target cells, such as the hepatocyte, is an attractive novel mechanism with the potential to explain the phenomena that we and others have reported, including the insulin-sensitizing, anti-apoptotic, pro-angiogenic and anti-inflammatory properties that have been attributed to adiponectin. We expect to significantly contribute to a better understanding of the clinical observations widely reported for adiponectin, as well as gain a better grasp of the tissue physiology of adipose tissue and its dysregulation in the pathological setting of obesity and type 2 diabetes.
Adiponectin has morphed into a widely used biomarker reflecting the health of adipose tissue and systemic insulin sensitivity - there is hardly a field n Endocrinology that has not been touched upon by the 12,000 papers published to date, and the observations reported are frequently amongst the most potent correlates to a wide variety of different conditions of metabolic dysregulation and other systemic pathological changes. This made adiponectin a mainstay clinical marker for a large number of disease states in many clinical studies. Despite the massive body of work that has been accomplished to date after nearly 20 years of work, we barely scratched the surface of the physiology of this intriguing factor, and the efforts outlined here will help elucidate the molecular mechanisms of action and the teleological reasons why a protein like adiponectin is needed to cope with metabolic stress.
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