SUMMARY FGF21, a member of the fibroblast growth factor (FGF) superfamily has recently emerged as a novel regulator of metabolism and energy utilization. However, the exact mechanism(s) whereby FGF21 mediates its actions have not been elucidated. There is considerable evidence that insulin resistance may arise from aberrant accumulation of intracellular lipids in insulin responsive tissues due to lipotoxicity. In particular the sphingolipid ceramide has been implicated in this process. Here, we show that FGF21 rapidly and robustly stimulates adiponectin secretion in rodents, while diminishing accumulation of ceramides in obese animals. Importantly, adiponectin knockout mice are refractory to changes in energy expenditure and ceramide-lowering effects evoked by FGF21 administration. Moreover, FGF21 lowers blood glucose levels and enhances insulin sensitivity in diabetic Lepob/ob mice and diet-induced obese (DIO) mice, only when adiponectin is functionally present. Collectively, these data suggest that FGF21 is a potent regulator of adiponectin secretion, and that FGF21 critically depends on adiponectin to exert its glycemic and insulin sensitizing effects.

Summary We have uncovered the existence of extracellular vesicle (EV)-mediated signaling between cell types within the adipose tissue (AT) proper. This phenomenon became evident in our attempts at generating an adipocyte-specific knock out of caveolin 1 (cav1) protein. While we effectively ablated the CAV1 gene in adipocytes, cav1 protein remained abundant. With the use of newly generated mouse models, we show that neighboring endothelial cells (ECs) transfer cav1-containing EVs to adipocytes in vivo, which reciprocate by releasing EVs to ECs. AT-derived EVs contain proteins and lipids capable of modulating cellular signaling pathways. Furthermore, this mechanism facilitates transfer of plasma constituents from ECs to the adipocyte. The transfer event is physiologically regulated by fasting/refeeding and obesity, suggesting EVs participate in the tissue response to changes in the systemic nutrient state. This work offers new insights into the complex signaling mechanisms that exist between adipocytes, stromal vascular cells and potentially distal organs.

Sphingolipids have garnered attention for their role in insulin resistance and lipotoxic cell death. Aberrant accumulation of ceramides correlates with hepatic insulin resistance and steatosis. To further investigate the tissue-specific effects of local changes in ceramidase activity, we have developed transgenic mice inducibly expressing acid ceramidase, to trigger the deacylation of ceramides. This represents the first inducible genetic model that acutely manipulates ceramides in adult mouse tissues. Hepatic overexpression of acid ceramidase prevents hepatic steatosis and prompts improvements in insulin action in liver and adipose tissue. Conversely, overexpression of acid ceramidase within adipose tissue prevents hepatic steatosis and insulin resistance. Induction of ceramidase activity in either tissue promotes a lowering of hepatic ceramides and reduced activation of the ceramide-activated protein kinase C isoform PKC-zeta. These observations suggest the existence of a rapidly acting "crosstalk" between liver and adipose tissue sphingolipids, critically regulating glucose metabolism and hepatic lipid uptake.

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