In the last 20 years, the view on adipose tissue has changed from a passive energy storing reservoir to a metabolically active endocrine organ. Adipose tissue secretes a wide variety of adipokines that regulate whole-body energy homeostasis. Among these factors, adiponectin (ADN) has been identified as one of the most potent regulators due to its anti-inflammatory, anti-apoptotic, and insulin sensitizing actions. Although circulating ADN promotes insulin sensitivity by decreasing gluconeogenesis and enhancing glucose uptake in peripheral tissues such as liver and muscle, the role of intracellular adipocyte ADN in metabolism is unclear. Transgenic expression of ADN lacking a portion of its N-terminal collagenous domain in mice (?-gly ADN) results in defective secretion of this mutant transgenic form of ADN, however, the ?-gly ADN mice also exhibit a chronic 3-fold increase of endogenous ADN in serum, along with the positive metabolic effects associated with ADN. This result suggests that intracellular ADN may exert important effects on adipose tissue directly through a postulated intracrine mechanism. In addition, carriers of the G45R polymorphism in the coding region of the ADN gene, found in Hispanic populations, have only 19% of normal circulating ADN. Surprisingly, these carriers maintain insulin sensitivity and glucose tolerance, which supports the notion of intracellular ADN possessing an active role in metabolism. To further address this issue, we have recently generated an inducible transgenic mouse model of the G45R polymorphism adiponectin (inducible G45R ADN). Since the G45R adiponectin polymorphism presents a unique dichotomy where hypoadiponectinemia is associated with a normal metabolic profile, we hypothesize that intracellular adiponectin is biologically active and integral to adiponectin's overall function in metabolic health. To test this hypothesis, I plan to determine whether inducible G45R ADN maintains insulin sensitivity when mice are metabolically challenged, determine how intracellular adiponectin mediates its effects in the adipocyte and identify the pathways involved in the degradation of intracellular adiponectin. Using a series of novel mouse models, I am well positioned to address these critical questions in a laboratory with established expertise on ADN action.