Leptin Signaling and Metabolic Regulation in Diabetes

Leptin is an adipokine primarily secreted by white adipose tissue that communicates energy status to the hypothalamus and peripheral organs. Binding of leptin to its receptor (LEPR) activates intracellular cascades—most notably the JAK/STAT and PI3K/Akt pathways—to suppress appetite, increase energy expenditure and modulate glucose and lipid metabolism. In healthy individuals this system maintains glucose homeostasis by enhancing insulin sensitivity in liver, muscle and adipose tissue, and by restraining hepatic gluconeogenesis. In obesity, chronically elevated leptin levels provoke central and peripheral leptin resistance, leading to impaired insulin action, dysregulated lipid handling and heightened inflammatory signalling. These perturbations contribute to the development and progression of type 2 diabetes. Recent research has elucidated mechanisms of leptin-induced glucose uptake in skeletal muscle, the contribution of local versus central receptor pools, and the therapeutic potential of leptin-derived peptides. Improved understanding of leptin resistance and interorgan crosstalk holds promise for novel interventions aimed at restoring metabolic balance in diabetes.

Research from Nature Portfolio

Central administration of leptin into the ventromedial hypothalamus was shown to enhance glucose uptake in red-type skeletal muscle via activation of sympathetic nerves and muscle β₂-adrenergic receptors, independently of AMPK activity. This work highlights a defined neural-to-muscle axis whereby leptin potentiates insulin signalling through norepinephrine turnover and insulin receptor phosphorylation in muscle. Complementary investigations employing genetic knockdown and reconstitution of LEPR in adipose tissue revealed that modification of receptor abundance within fat depot exerts substantial effects on systemic glucose tolerance and insulin secretion. Mice lacking adipose LEPR exhibited altered insulin profiles upon glucose challenge and differed in their glycaemic response to prolonged leptin therapy under insulin-deficient conditions. These findings delineate the distinct metabolic roles of central versus peripheral leptin signalling and emphasise the capacity of adipose-resident receptors to shape whole-body glucose homeostasis.

Leptin Signaling and Metabolic Regulation in Diabetes publication trend

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

Technical terms

Leptin: A hormone secreted by adipose tissue that regulates appetite, energy expenditure and glucose metabolism.

Adipokine: A bioactive peptide produced by fat cells that influences metabolic and inflammatory processes.

Leptin receptor (LEPR): A cell-surface receptor that mediates leptin’s effects on central and peripheral tissues.

JAK/STAT pathway: A signal transduction cascade activated by leptin binding, leading to gene transcription changes.

AMPK: An energy sensor kinase that promotes glucose uptake and fatty acid oxidation under low-energy conditions.

β₂-adrenergic receptor: A sympathetic nervous system receptor in muscle that modulates glucose uptake in response to leptin-induced nerve activity.

Insulin resistance: A diminished response of tissues to insulin’s action, resulting in impaired glucose uptake and elevated blood glucose.

References

1. Changes in Lipid Metabolism Enzymes in Rat Epididymal Fat after Chronic Central Leptin Infusion Are Related to Alterations in Inflammation and Insulin Signaling. International Journal of Molecular Sciences (2023).
2. Across-species benefits of adrenalectomy on congenital generalized lipoatrophic diabetes: a review. Frontiers in Endocrinology (2024).
3. A peptide derived from the amino terminus of leptin improves glucose metabolism and energy homeostasis in myotubes and db/db mice. Journal of Biological Chemistry (2024).
4. Induction of glucose uptake in skeletal muscle by central leptin is mediated by muscle β2-adrenergic receptor but not by AMPK. Scientific Reports (2017).
5. Metabolic effects of leptin receptor knockdown or reconstitution in adipose tissues. Scientific Reports (2019).