ADORA-driven brain-sympathetic neuro-adipose connections control body weight and adipose lipid metabolism.

It is essential to elucidate brain-adipocyte interactions in order to tackle obesity and its comorbidities, as the precise control of brain-adipose tissue cross-talk is crucial for energy and glucose homeostasis. Recent studies show that in the peripheral adipose tissue, adenosine induces adipogenesis through peripheral adenosine A receptor (pADORA) signaling; however, it remains unclear whether systemic and adipose tissue metabolism would also be under the control of central (c) ADORA signaling. Here, we use tissue-specific pharmacology and metabolic tools to clarify the roles of cADORA signaling in energy and adipocyte physiology. We found that cADORA signaling reduces body weight while also inducing adipose tissue lipolysis. cADORA signaling also increases adipose tissue sympathetic norepinephrine content. In contrast, pADORA signaling facilitates a high-fat diet-induced obesity (DIO). We propose here a novel mechanism in which cADORA and pADORA signaling hinder and aggravate DIO, respectively.