Leptin Signaling and Energy Homeostasis in Obesity

Leptin, a hormone secreted by adipose tissue, communicates body fat stores to the brain and orchestrates appetite, energy expenditure and neuroendocrine function. Binding of leptin to its long-form receptor (LepRb) in hypothalamic neurons triggers intracellular pathways—most notably JAK2–STAT3—that suppress feeding and promote energy utilisation. In obesity, high circulating leptin levels coincide with diminished receptor sensitivity, a phenomenon known as leptin resistance, which perpetuates weight gain and metabolic dysfunction. Emerging structural and mechanistic studies reveal how receptor conformation, post-receptor feedback inhibitors and epigenetic regulators converge to impair signalling. Parallel work in animal models has identified modifiers of leptin transport across the blood–brain barrier, cell-specific transcriptional repressors and adaptor proteins that determine receptor abundance. Together, these insights illuminate the complex network that underlies impaired leptin action in obesity and point to strategies for restoring leptin sensitivity and improving metabolic health.

Research from Nature Portfolio

Recent studies have resolved the three-dimensional architecture of the leptin-bound LepRb complex, uncovering an asymmetric dimerisation mode in which a single leptin molecule engages two distinct receptor interfaces. This structural map explains how common human obesity-associated mutations disrupt receptor activation and highlights sites for engineering biased agonists. Such designer leptin variants can selectively modulate STAT3 phosphorylation, decouple negative regulatory feedback loops and restore anorectic signalling in models of leptin resistance. These advances provide a blueprint for next-generation leptin analogues with improved efficacy in obese individuals.

Leptin Signaling and Energy Homeostasis in Obesity publication trend

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

Technical terms

Leptin: A peptide hormone produced by adipocytes that signals energy sufficiency to the brain.

Leptin resistance: A state in which high leptin levels fail to suppress appetite or increase energy expenditure.

Long-form leptin receptor (LepRb): The signalling-competent isoform that activates JAK2–STAT3 pathways in the hypothalamus.

STAT3: A transcription factor phosphorylated downstream of LepRb that mediates appetite suppression.

Epigenetic reprogramming: Modifications of DNA or histones that alter gene expression without changing the nucleotide sequence.

Endospanin 1: A receptor-associated protein that regulates cell-surface abundance and trafficking of the leptin receptor.

References

1. Structural insights into the mechanism of leptin receptor activation. Nature Communications (2023).
2. LepRb cell-specific deletion of Slug mitigates obesity and NAFLD. Journal of Clinical Investigation (2023).
3. Whole-body deletion of Endospanin 1 protects from obesity-associated deleterious metabolic alterations. JCI Insight (2024).