Fabp4, a new player in the adipo-pancreatic axis

As an early hallmark of type 2 diabetes, the associated insulin resistance in peripheral tissues demands extra insulin production from the pancreatic b cells. Circulating glucose has long been recognized as the primary messenger, triggering acute and prolonged insulin secretion via well-defined biochemical pathways in b cells. However, additional mechanisms are in place to safeguard against lagging islet mass and function. Recent efforts have cast light on the crosstalk between peripheral tissues and b cells, mediated by specific protein factors. Skeletal muscle, in the absence of PGC-1a, releases excessive levels of pro-inflammatory IL-6 to blunt the glucose-stimulated insulin secretion (GSIS) from islets [1]. Others report that upon exposure to TNF-a, insulin-resistant myocytes release a panel of cytokines that impair GSIS, while normal muscle cells produce hormones that are beneficial to b cell function and proliferation [2]. As for factors derived from the liver and adipose tissue, Angptl8 (a.k.a. betatrophin) has been implicated as a possible stimulator of b cell proliferation [3], though the relevance of this finding for human islet proliferation has recently been questioned [4]. In this issue of Molecular Metabolism, Cantley and colleagues report a novel role of the adipocyte-specific fatty acid-binding protein Fabp4 (aP2) in mediating b cell GSIS [5]. This group set out to test the hypothesis that upon obesity and hypoxia, adipose tissues convey signals to pancreatic b cells to indicate the need for enhanced insulin production. This adipocyte-derived signal would account for, at least in part, the hyperinsulinemia observed during insulin resistance. With mass spectrometry analysis of the proteins in the conditioned medium of 3T3-L1 adipocytes, the authors identified a small number of proteins that were both secreted and upregulated under hypoxic conditions. Sparcl1 and the a1 subunit of collagen VI were amongst them. Both of these are extracellular matrix proteins, presumably active only in the local microenvironment and seemingly ill-suited as an endocrine signal. Future studies will have to address whether these factors or cleavage products of these proteins may serve as signals at the systemic level. A lower-hanging fruit amongst these hypoxia-induced proteins was Fabp4. Even though conventionally thought of as an intracellular, cytoplasmic protein, there is considerable momentum for the idea that Fabp4 has the potential to be a secreted molecule as well, even though its cellular release is not mediated through the conventional secretory pathway. Fabp4 had previously been implicated as a potent stimulator of b3-adrenergic agonist action, leading to stimulated acute insulin secretion [6]. This suggested that Fabp4 may serve