Metabolic Regulation of Body Weight Homeostasis

Metabolic regulation of body weight homeostasis emerges from a complex interplay between energy intake, storage and expenditure, orchestrated by endocrine and neural networks. Central integration of peripheral signals—such as adipose-derived leptin, gut peptides and hepatokines—occurs in hypothalamic centres that balance orexigenic and anorexigenic pathways. Adipose tissue serves as both an energy reservoir and an endocrine organ, secreting adipokines that modulate appetite and whole-body metabolism. The melanocortin pathway, including melanocortin 4 receptor (MC4R), translates leptin signalling into changes in food consumption and thermogenesis. Non-shivering thermogenesis in brown and beige adipose depots, driven by uncoupling proteins, contributes to energy dissipation. Emerging evidence for a mechanical sensor, the gravitostat, implies that skeletal loading influences fat mass independently of known hormonal circuits. Additional homeostatic layers include hepatic factors such as fibroblast growth factor 21 (FGF21) and recently identified proteases that counterbalance overfeeding. Evolutionary frameworks propose a dual-intervention point system, which allows safe variations in adiposity until lower or upper defence thresholds are breached. Dysregulation of these networks underpins obesity and cachexia, while modulation of key effectors offers therapeutic potential. Practical applications extend from dietary manipulation to loading-based interventions and targeted modulation of central pathways, with global implications for addressing obesity and metabolic disorders.

Research from Nature Portfolio

Recent studies have uncovered mechanisms that defend against overfeeding-induced weight gain, independent of classical hormonal mediators. In diet-induced obese murine models, sustained inhibition of voluntary food intake following caloric excess occurs without requirement for FGF21 or MC4R signalling. Proteomic analysis revealed elevated circulating legumain, and administration of recombinant legumain led to reductions in body weight and food intake alongside decreased vascularisation in the hypothalamus and suppressed expression of orexigenic neuropeptides. Furthermore, compensatory homeostatic responses to overfeeding were preserved in MC4R-knockout animals, highlighting alternative central or peripheral factors in body weight defence. These findings broaden the landscape of overfeeding resilience and identify novel candidates for therapeutic exploration.

Metabolic Regulation of Body Weight Homeostasis publication trend

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

Technical terms

Homeostasis: The dynamic process by which physiological variables are maintained within defined limits.

Adipokine: Bioactive protein secreted by adipose tissue that influences metabolism and inflammation.

Orexigenic neuropeptide: Central signalling molecule that stimulates appetite.

Leptin: Adipose-derived hormone that signals energy sufficiency to the brain.

Fibroblast growth factor 21 (FGF21): Hepatic hormone involved in adaptive thermogenesis and nutrient sensing.

Melanocortin 4 receptor (MC4R): Hypothalamic receptor essential for translating energy-balance signals into satiety responses.

Gravitostat: Proposed mechanosensory system by which skeletal loading regulates fat mass.

Dual-intervention point system: Evolutionary model suggesting upper and lower thresholds govern body fat control.

References

1. Protection against overfeeding-induced weight gain is preserved in obesity but does not require FGF21 or MC4R. Nature Communications (2024).
2. Beyond BMI. Nutrients (2023).
3. Increased weight loading reduces body weight and body fat in obese subjects – A proof of concept randomized clinical trial. EClinicalMedicine (2020).
4. The unidentified hormonal defense against weight gain. PLOS Biology (2020).
5. Obesity: an evolutionary context. Life Metabolism (2022).