Leptin Modulation and Its Impact on Metabolic Disorders

Leptin is a hormone secreted by adipocytes that signals nutritional status to the central nervous system, orchestrating energy balance by regulating appetite, energy expenditure and glucose homeostasis. Modulation of leptin levels and signalling involves both alterations in receptor expression and the generation of circulating binding proteins, notably the soluble leptin receptor, which together determine leptin bioavailability and action. In states of obesity and type 2 diabetes, the paradox of elevated leptin concentrations alongside impaired metabolic response, termed leptin resistance, underscores the complexity of leptin pathways. Mechanisms contributing to leptin resistance include receptor downregulation, ectodomain shedding of membrane-bound receptors, competitive binding by circulating proteins and inflammatory interference. Emerging data implicate these processes in the pathophysiology of metabolic disorders and offer targets for therapeutic intervention, such as receptor sensitisation, modulation of shedding enzymes and neutralisation of inhibitory binding proteins. Advances in understanding the molecular interplay of leptin signalling have broad implications for managing obesity, diabetes and related cardiometabolic conditions.

Research from Nature Portfolio

Recent studies have explored longitudinal relationships between body mass index and trajectories of obesity-related biomarkers, including leptin amongst other adipokines, in healthy women. Analyses reveal that increases in adiposity precede changes in obesity-related protein scores, suggesting that rising leptin levels may both reflect and drive alterations in cardiometabolic risk profiles. Cross-lagged path models indicate directional influences from body fat accumulation towards elevated protein markers relevant to insulin resistance and metabolic syndrome, underscoring the role of leptin-driven pathways in mediating downstream metabolic dysfunction. This work highlights the temporal ordering of weight gain and leptin modulation in contributing to disease risk, and suggests weight management may attenuate adverse biomarker trajectories.

Leptin Modulation and Its Impact on Metabolic Disorders publication trend

The graph below shows the total number of articles in leptin modulation and its impact on metabolic disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Leptin: An adipocyte-derived hormone that regulates appetite, energy expenditure and glucose metabolism by signalling nutritional status to the brain.

Leptin receptor (Ob-R): A cell-surface receptor that mediates leptin signalling; exists in multiple splice isoforms including long forms capable of intracellular signalling.

Soluble leptin receptor (sOb-R): The extracellular domain of Ob-R released into circulation, which binds leptin and modulates its bioavailability.

Free leptin index (FLI): The ratio of circulating leptin to soluble leptin receptor, used as an indicator of leptin bioactivity and resistance.

Leptin resistance: A state in which elevated leptin levels fail to elicit normal metabolic responses, contributing to obesity and glucose intolerance.

C-reactive protein (CRP): An acute-phase inflammatory protein that can interact with the leptin receptor and influence leptin signalling in obesity.

References

1. Triglycerides and leptin soluble receptor: Which one is the target to protect β-cells in patients with type 2 diabetes?. Frontiers in Endocrinology (2023).
2. C-Reactive Protein (CRP) and Leptin Receptor in Obesity: Binding of Monomeric CRP to Leptin Receptor. Frontiers in Immunology (2018).
3. The role of leptin in the control of insulin-glucose axis. Frontiers in Neuroscience (2013).
4. Temporal relationships between BMI and obesity-related predictors of cardiometabolic and breast cancer risk in a longitudinal cohort. Scientific Reports (2023).
5. Modulation of Circulating Leptin Levels by Its Soluble Receptor*. Journal of Biological Chemistry (2000).
6. Generation of Soluble Leptin Receptor by Ectodomain Shedding of Membrane-spanning Receptors in Vitro and in Vivo *. Journal of Biological Chemistry (2002).