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With the prevalence of obesity and associated comorbidities, studies aimed at revealing mechanisms that regulate energy homeostasis have gained increasing interest. In 1994, the cloning of leptin was a milestone in metabolic research. As an adipocytokine, leptin governs food intake and energy homeostasis through leptin receptors (LepR) in the brain. The failure of increased leptin levels to suppress feeding and elevate energy expenditure is referred to as leptin resistance, which encompasses complex pathophysiological processes. Within the brain, LepR-expressing neurons are distributed in hypothalamus and other brain areas, and each population of the LepR-expressing neurons may mediate particular aspects of leptin effects. In LepR-expressing neurons, the binding of leptin to LepR initiates multiple signaling cascades including janus kinase (JAK)–signal transducers and activators of transcription (STAT) phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT), extracellular regulated protein kinase (ERK), and AMP-activated protein kinase (AMPK) signaling, etc., mediating leptin actions. These findings place leptin at the intersection of metabolic and neuroendocrine regulations, and render leptin a key target for treating obesity and associated comorbidities. This review highlights the main discoveries that shaped the field of leptin for better understanding of the mechanism governing metabolic homeostasis, and guides the development of safe and effective interventions to treat obesity and associated diseases.

The RIIβ subunit of cAMP‐dependent protein kinase A (PKA) is expressed in the brain and adipose tissue. RIIβ‐knockout mice show leanness and increased UCP1 in brown adipose tissue. The authors have previously reported that RIIβ reexpression in hypothalamic GABAergic neurons rescues the leanness. However, whether white adipose tissue (WAT) browning contributes to the leanness and whether RIIβ‐PKA in these neurons governs WAT browning are unknown. Here, this work reports that RIIβ‐KO mice exhibit a robust WAT browning. RIIβ reexpression in dorsal median hypothalamic GABAergic neurons (DMH GABAergic neurons) abrogates WAT browning. Single‐cell sequencing, transcriptome sequencing, and electrophysiological studies show increased GABAergic activity in DMH GABAergic neurons of RIIβ‐KO mice. Activation of DMH GABAergic neurons or inhibition of PKA in these neurons elicits WAT browning and thus lowers body weight. These findings reveal that RIIβ‐PKA in DMH GABAergic neurons regulates WAT browning. Targeting RIIβ‐PKA in DMH GABAergic neurons may offer a clinically useful way to promote WAT browning for treating obesity and other metabolic disorders. [ABSTRACT FROM AUTHOR]