Leptin Signaling in Metabolic Regulation

Leptin is an adipocyte‐derived hormone that communicates peripheral energy stores to the central nervous system, chiefly via the long form of the leptin receptor in the hypothalamus. Upon binding, leptin activates JAK/STAT, PI3K and MAPK cascades, leading to changes in neuropeptide expression (for example pro-opiomelanocortin and agouti-related peptide) that suppress appetite and increase energy expenditure. Beyond central effects, leptin modulates glucose uptake, lipid oxidation and insulin sensitivity in peripheral tissues, and influences immune function and reproductive axes. A key regulatory checkpoint is provided by suppressor of cytokine signalling proteins, notably SOCS3, which attenuate receptor signalling. In conditions of energy surplus, elevated leptin levels coincide with leptin resistance—impaired receptor signalling despite high hormone concentrations—contributing to obesity and metabolic syndrome. Emerging evidence also highlights local production of leptin and its receptors in non-adipose tissues, suggesting autocrine/paracrine circuits that refine metabolic and neuroendocrine responses.

Research from Nature Portfolio

Recent studies have uncovered an intrapituitary adipokine network in primates, revealing that leptin produced within the anterior pituitary acts alongside circulating leptin to regulate hormone release. In primary pituitary cultures, leptin stimulated growth hormone and prolactin secretion via activation of cAMP/PKA and PLC/PKC pathways, while adiponectin exerted inhibitory effects on GH. Distinct downstream signalling modules, including PI3K/MAPK/mTOR and calcium‐dependent mechanisms, were shown to govern cell‐type‐specific responses. This work establishes that local adipokine production and receptor expression in the pituitary contribute to the fine-tuning of endocrine axes central to metabolic homeostasis.

Leptin Signaling in Metabolic Regulation publication trend

The graph below shows the total number of articles in leptin signaling in metabolic regulation across all publications each year (not limited to Nature Index journals).

Technical terms

Leptin: A hormone secreted by fat cells that signals energy sufficiency and regulates appetite and metabolism.

Leptin receptor (LEPR): A cell-surface receptor with multiple isoforms; the long form (LRb) transduces full intracellular signalling.

JAK/STAT pathway: A cascade activated by cytokine receptors, including LRb, resulting in transcriptional regulation of target genes.

Suppressor of cytokine signalling 3 (SOCS3): An intracellular feedback inhibitor that dampens cytokine receptor signalling.

Adipokine: A biologically active peptide produced by adipose tissue that modulates metabolic, inflammatory and endocrine processes.

References

1. Adipokines (Leptin, Adiponectin, Resistin) Differentially Regulate All Hormonal Cell Types in Primary Anterior Pituitary Cell Cultures from Two Primate Species. Scientific Reports (2017).
2. Influence of Leptin on the Secretion of Growth Hormone in Ewes under Different Photoperiodic Conditions. International Journal of Molecular Sciences (2023).
3. Seasonal and nutritional changes in the short form of the leptin receptor expression and VEGF system in the choroid plexus, arcuate nucleus, and anterior pituitary in MTS-leptin and resistin-treated sheep. Frontiers in Neuroscience (2023).