Studies Defining The Local Function of Adipose Tissue IGF1 And The Role of Lipolysis in Adipose Tissue Macrophage Lipid Uptake

Adipose tissue serves as the primary storage depot for excess calories in mammals and its normal development and the efficient storage and release triglycerides are necessary to maintain systemic metabolism. Well studied factors that shape the development and metabolic function of adipose tissue include anabolic hormones, e.g. insulin and glucocorticoids, and circulating catabolic factors, e.g. glucagon and catecholamines. Less well defined are the roles of local factors that shape adipose tissue development and function. Here we have studied the role of locally produced insulin-like growth factor-1 (IGF1) on adipose tissue development and lipolysis. We found that expression of Igf1 by adipose tissue is derived from multiple cell types including adipocytes and macrophages. The expression of adipose tissue Igf1 is maintained at a constant level during the development of obesity despite the large influx of macrophages. This occurs because as adipocytes undergo hypertrophy their expression of Igf1 is reduced. Targeted deletion of Igf1 from adipocytes, macrophages or both cells reveals that adipocyte-derived IGF1 is required for hyperplasia of adipocytes in intra-abdominal but not subcutaneous depots during the development of obesity and that macrophage-derived IGF1 maintains adipose tissue mass of intra-abdominal fat during a thermogenic challenge. We did not detect any systemic metabolic effect of cell-specific deletion of Igf1 but found evidence of fibrosis in livers of obese mice that lack myeloid IGF1. As an independent study, we investigated the role of lipolysis in lipid uptake by adipose tissue macrophages (ATMs). We previously reported that lipolysis regulates ATM recruitment to fat. In addition, a recent study revealed that ATMs accumulate neutral lipid and contribute to adipose tissue metabolism by activating lysosomal-dependent program. However, in obese mice neutral lipids accumulate in membrane bound vesicles, i.e. not lipid droplets. This raises the possibility that neutral lipids accumulate in ATMs in a lipolysis independent manner, through a process of endocytosis. To address whether lipid uptake in ATM is dependent upon adipocyte lipolysis, we generated mice that lacked the neutral lipase required for adipocyte lipolysis (PNPLA2/ATGL). Adipocyte-specific deletion of Pnpla2 markedly reduced the accumulation of lipid in ATMs from lean and obese mice arguing that adipose PNPLA2-dependent lipolysis modulates ATM lipid uptake in both lean and obese animals. These findings argue that local interactions among cell populations in adipose tissue are important in regulating both development and metabolic function of adipose tissue mass, and that more detailed studies of the paracrine interactions offer the possibility of identifying pathways that will prove therapeutically tractable