To fulfill its role as the major energy-storing tissue, adipose has several unique properties that cannot be seen in any other organ, including an almost unlimited capacity to expand in a non-transformed state. As such, the tissue requires potent mechanisms to remodel, acutely and chronically. Adipocytes can rapidly reach the diffusional limit of oxygen during growth; hypoxia is therefore an early determinant that limits healthy expansion. Proper expansion requires a highly coordinated response among many different cell types, including endothelial precursor cells, immune cells, and preadipocytes. There are therefore remarkable similarities between adipose expansion and growth of solid tumors, a phenomenon that presents both an opportunity and a challenge, since pharmacological interventions supporting healthy adipose tissue adaptation can also facilitate tumor growth.

The protein hormone adiponectin is known to have many beneficial systemic effects, including promoting cell survival, anti-inflammation and insulin sensitivity. Phil Scherer and his colleagues have found that these pleiotropic effects are mediated by a ceramidase activity associated with the two known isoforms of the adiponectin receptor. The adipocyte-derived secretory factor adiponectin promotes insulin sensitivity, decreases inflammation and promotes cell survival. No unifying mechanism has yet explained how adiponectin can exert such a variety of beneficial systemic effects. Here, we show that adiponectin potently stimulates a ceramidase activity associated with its two receptors, AdipoR1 and AdipoR2, and enhances ceramide catabolism and formation of its antiapoptotic metabolite—sphingosine-1-phosphate (S1P)—independently of AMP-dependent kinase (AMPK). Using models of inducible apoptosis in pancreatic beta cells and cardiomyocytes, we show that transgenic overproduction of adiponectin decreases caspase-8-mediated death, whereas genetic ablation of adiponectin enhances apoptosis in vivo through a sphingolipid-mediated pathway. Ceramidase activity is impaired in cells lacking both adiponectin receptor isoforms, leading to elevated ceramide levels and enhanced susceptibility to palmitate-induced cell death. Combined, our observations suggest a unifying mechanism of action for the beneficial systemic effects exerted by adiponectin, with sphingolipid metabolism as its core upstream signaling component.

Obese fat pads are frequently undervascularized and hypoxic, leading to increased fibrosis, inflammation, and ultimately insulin resistance. We hypothesized that VEGF-A–induced stimulation of angiogenesis enables sustained and sufficient oxygen and nutrient exchange during fat mass expansion, thereby improving adipose tissue function. Using a doxycycline (Dox)-inducible adipocyte-specific VEGF-A overexpression model, we demonstrate that the local up-regulation of VEGF-A in adipocytes improves vascularization and causes a “browning” of white adipose tissue (AT), with massive up-regulation of UCP1 and PGC1α. This is associated with an increase in energy expenditure and resistance to high fat diet-mediated metabolic insults. Similarly, inhibition of VEGF-A–induced activation of VEGFR2 during the early phase of high fat diet-induced weight gain, causes aggravated systemic insulin resistance. However, the same VEGF-A–VEGFR2 blockade in ob/ob mice leads to a reduced body-weight gain, an improvement in insulin sensitivity, a decrease in inflammatory factors, and increased incidence of adipocyte death. The consequences of modulation of angiogenic activity are therefore context dependent. Proangiogenic activity during adipose tissue expansion is beneficial, associated with potent protective effects on metabolism, whereas antiangiogenic action in the context of preexisting adipose tissue dysfunction leads to improvements in metabolism, an effect likely mediated by the ablation of dysfunctional proinflammatory adipocytes.