Neuregulins in Metabolic Regulation and Adipose Tissue Physiology

Neuregulins comprise a family of epidermal growth factor-like ligands that signal via ErbB receptor tyrosine kinases to coordinate diverse cellular processes. Among them, Neuregulin-4 (NRG4) has emerged as a key adipose-derived hormone that engages in inter-organ communication to regulate glucose and lipid metabolism. NRG4 expression is enriched in brown and beige adipocytes and is dynamically regulated by nutritional and thermal stimuli. In peripheral tissues, NRG4 promotes fuel oxidation, attenuates lipogenesis and hepatic steatosis, and modulates adipokine profiles to improve systemic insulin sensitivity. In the central nervous system, NRG4 activates hypothalamic ErbB4 receptors on oxytocin neurons, thereby adjusting feeding behaviour and energy expenditure. Beyond adipose tissue, classical Neuregulin-1 isoforms influence skeletal muscle glucose uptake by facilitating GLUT4 translocation via PI3K/AKT-dependent cascades. Altogether, Neuregulins serve as multifunctional mediators that integrate thermogenic, inflammatory and neuroendocrine circuits to preserve metabolic homeostasis. Their broad therapeutic potential spans obesity, type 2 diabetes and related cardiometabolic disorders.

Research from Nature Portfolio

Hydrodynamic gene transfer of Neuregulin-4 in rodents has been shown to prevent high-fat diet-induced weight gain without altering established adiposity. Overexpression of NRG4 suppressed hepatic lipogenesis and PPARγ-mediated lipid storage, reduced macrophage infiltration in adipose depots and lowered pro-inflammatory markers. These changes collectively enhanced insulin sensitivity and mitigated fatty liver development. In human cohorts of obese adults, circulating NRG4 concentrations were inversely associated with markers of subclinical atherosclerosis. Individuals with lower serum NRG4 exhibited greater carotid intima-media thickness and plaque prevalence, indicating that adipokine-derived NRG4 may serve as a biomarker for cardiovascular risk and a target for early intervention.

Neuregulins in Metabolic Regulation and Adipose Tissue Physiology publication trend

The graph below shows the total number of articles in neuregulins in metabolic regulation and adipose tissue physiology across all publications each year (not limited to Nature Index journals).

Technical terms

Neuregulins: A family of growth factor–like proteins that bind ErbB receptors to regulate cell growth, differentiation and metabolic signalling.

ErbB4 receptor: A member of the ErbB tyrosine kinase receptor family that mediates Neuregulin signalling in neural and peripheral tissues.

Adipokine: A bioactive peptide or protein secreted by adipose tissue that exerts autocrine, paracrine or endocrine effects on metabolism.

Beige adipocyte: A thermogenically competent cell type within white adipose depots that expresses uncoupling protein-1 upon appropriate stimuli.

Thermogenesis: The process by which energy is dissipated as heat, often mediated by uncoupling proteins in brown or beige fat.

PI3K/AKT signalling pathway: A key intracellular cascade initiated by receptor tyrosine kinases that regulates glucose uptake, cell survival and metabolic functions.

References

1. Neuregulin4 Acts on Hypothalamic ErBb4 to Excite Oxytocin Neurons and Preserve Metabolic Homeostasis. Advanced Science (2023).
2. Neuregulin 4 mediates the metabolic benefits of mild cold exposure by promoting beige fat thermogenesis. JCI Insight (2024).
3. Neuregulin-1β increases glucose uptake and promotes GLUT4 translocation in palmitate-treated C2C12 myotubes by activating PI3K/AKT signaling pathway. Frontiers in Pharmacology (2023).
4. Nrg4 promotes fuel oxidation and a healthy adipokine profile to ameliorate diet-induced metabolic disorders. Molecular Metabolism (2017).
5. Preventing High Fat Diet-induced Obesity and Improving Insulin Sensitivity through Neuregulin 4 Gene Transfer. Scientific Reports (2016).
6. Circulating neuregulin 4 levels are inversely associated with subclinical cardiovascular disease in obese adults. Scientific Reports (2016).