The sympathetic nervous system (SNS) is a key regulator of the metabolic and endocrine functions of adipose tissue. Increased SNS outflow promotes fat mobilization, stimulates non-shivering thermogenesis, promotes browning, and inhibits leptin production. Most of these effects are attributed to norepinephrine activation of the Gs-coupled beta 3 adrenergic receptors (ADRB3) located on the surface of the adipocytes. However, evidence suggests that other adrenergic receptor subtypes, including the Gi-coupled alpha 2a adrenergic receptors (ADRA2A) and the Gs-coupled beta 1 adrenergic receptors (ADRB1), also might mediate the SNS effects on adipose tissues.
In an effort to understand the specific adrenergic receptor subtypes mediating the SNS function on adipose tissue, we engineered mice harboring conditional alleles of the adrenergic receptors and generated mice that lack Adrb1, Adrb3 or Adra2a selectively in adipocytes. We also harness the power of chemogenetics to develop unique mouse models allowing the specific and spatiotemporal stimulation of adipose tissue Gi and Gs signaling.
Combining pharmacology with these novel genetic tools, we show that Gs-signaling through both ADRB1 and ADRB3 regulate glucose homeostasis, while the balance between ADRA2A Gi-signaling and ADRB3 Gs-signaling determines leptin production. Supporting these conclusions, chemogenetic activation of Gs signaling in adipocytes induced rapid and sustained hypoglycemia. These hypoglycemic effects were secondary to increased insulin release, likely consequent to increased lipolysis. In contrast, acute stimulation of Gi signaling in adipose tissue did not affect glucose metabolism or lipolysis, but regulated leptin production.
Collectively, our results indicate that the SNS regulation of adipose endocrine and metabolic functions is mediated by multiple pathways. Our data also highlight the usefulness of chemogenetic technology to better understand adipocytes functions.