Adipocyte β3-adrenergic receptor signaling attenuates leptin production but is dispensable for fasting induced leptin...

Leptin, secreted by adipocytes, conveys the status of peripheral energy stores to the brain to regulate appetite and metabolism. Although sympathetic activation via β3-adrenergic receptors (β3-ARs) has been shown to suppress leptin expression, it remains unclear whether this regulation arises directly within adipocytes or through other populations. In addition, it is unclear whether β3-AR signaling contributes to the fasting-induced reduction in leptin. To address this, we generated a novel Adrb3 transcriptional block mouse (Adrb3^TB/TB) enabling global β3-AR inactivation and adipocyte-specific reexpression (Adrb3^TB/TB; Adipoq-Cre). Global loss of Adrb3 increased plasma leptin levels, whereas reexpression in adipocytes normalized leptin and restored β3-AR agonist-induced leptin suppression. Analysis of Lep mRNA revealed depot-specific regulation, with β3-AR signaling predominantly affecting gonadal and subcutaneous white adipose tissue, whereas brown adipose tissue responses were modest and variable. Despite these effects, fasting for 48 h comparably reduced plasma leptin and Lep mRNA in both wild-type (WT) and Adrb3^TB/TB mice, indicating that β3-AR signaling is not required for the fasting-induced decline in leptin. Collectively, these findings establish adipocyte β3-AR signaling as a key regulator that constrains leptin synthesis under basal and stimulated conditions in male mice, but not during energy deprivation. Together, these findings clarify the role of adipocyte β3-adrenergic signaling in leptin regulation and provide new insight into the sympathetic control of adipose tissue function.NEW & NOTEWORTHY This study introduces a novel Adrb3 transcriptional block mouse model that enables global inactivation or adipocyte-specific reexpression of β3-adrenergic receptor signaling. Using this approach, we demonstrate that adipocyte β3-adrenergic signaling directly restrains leptin production under basal and stimulated conditions but is dispensable for fasting-induced leptin suppression. These findings refine the role of sympathetic signaling in adipose tissue and clarify mechanisms governing leptin regulation.