Decoding the Sympathetic Nervous System's Regulation of White Adipose Tissue Hyperplasia

Adipose tissue (AT) expands via both hypertrophy and hyperplasia during the development of obesity. While AT hypertrophy involves the increase in size of existing adipocytes, hyperplasia is the process of creating new adipocytes from the pool of adipocyte precursor cells (APCs) which includes adipocyte progenitor cells and preadipocytes. Prior studies have implicated a role of the sympathetic nervous system (SNS) in regulation of hyperplasia in white adipose tissue (WAT). These studies were not specific to APCs, however, and lacked characterization of the signaling intermediaries. Here we aimed to determine the mechanisms underlying SNS regulation of APC proliferation in WAT. Using flow cytometry with antibodies against various cell surface markers, along with an intracellular marker of proliferation (Ki67), we quantitated the percentages and proliferative status of adipocyte progenitor cells and preadipocytes in the stromal vascular fraction (SVF) of WAT. In vivo SNS activation through cold exposure, as well as in vitro adrenergic stimulation via exposure to the canonical SNS neurotransmitter norepinephrine (NE), inhibited preadipocyte proliferation. Pretreatment with propranolol, a ?1- and ?2-adrenergic receptor (AR) antagonist, rescued the inhibitory effects of NE in primary cell culture. The selective ?1-AR agonist dobutamine diminished preadipocyte proliferation both in vivo and in vitro, whereas the selective ?2-AR agonist, salbutamol, promoted proliferation in vitro, suggesting that the ?1-AR may mediate the inhibitory effect of NE on preadipocyte proliferation. We further explored the downstream signaling by pretreating cultured SVF cells with an adenosine monophosphate-activated protein kinase (AMPK) blocker, Compound C (CC). CC prevented the inhibitory effect of dobutamine on preadipocyte proliferation as compared with relative controls. Taken together, we conclude that SNS activation suppresses WAT preadipocyte proliferation via the ?1-AR and that downstream signaling may include AMPK activation.