CNS β₃-adrenergic receptor activation regulates feeding behavior, white fat browning, and body weight

Pharmacological β₃-adrenergic receptor (β₃AR) activation leads to increased mitochondrial biogenesis and activity in white adipose tissue (WAT), a process commonly referred to as "browning", and transiently increased insulin release. These effects are associated with improved metabolic function and weight loss. It is assumed that this impact of β₃AR agonists is mediated solely through activation of β₃ARs in adipose tissue. However, β₃ARs are also found in the brain, in areas such as the brain stem and the hypothalamus, which provide multisynaptic innervation to brown and white adipose depots. Thus, contrary to the current adipocentric view, the central nervous system (CNS) may also have the ability to regulate energy balance and metabolism through actions on central β₃ARs. Therefore, this study aimed to elucidate whether CNS β₃ARs can regulate browning of WAT and other aspects of metabolic regulation, such as food intake control and insulin release. We found that acute central injection of β₃AR agonist potently reduced food intake, body weight, and increased hypothalamic neuronal activity in rats. Acute central β₃AR stimulation was also accompanied by a transient increase in circulating insulin levels. Moreover, subchronic central β₃AR agonist treatment led to a browning response in both inguinal (IWAT) and gonadal WAT (GWAT), along with reduced GWAT and increased BAT mass. In high-fat, high-sugar-fed rats, subchronic central β₃AR stimulation reduced body weight, chow, lard, and sucrose water intake, in addition to increasing browning of IWAT and GWAT. Collectively, our results identify the brain as a new site of action for the anorexic and browning impact of β₃AR activation.