ADORA₁-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 A₁ receptor (pADORA₁) signaling; however, it remains unclear whether systemic and adipose tissue metabolism would also be under the control of central (c) ADORA₁ signaling. Here, we use tissue-specific pharmacology and metabolic tools to clarify the roles of cADORA₁ signaling in energy and adipocyte physiology. We found that cADORA₁ signaling reduces body weight while also inducing adipose tissue lipolysis. cADORA₁ signaling also increases adipose tissue sympathetic norepinephrine content. In contrast, pADORA₁ signaling facilitates a high-fat diet-induced obesity (DIO). We propose here a novel mechanism in which cADORA₁ and pADORA₁ signaling hinder and aggravate DIO, respectively.