JNK Signaling Pathways in Obesity and Insulin Resistance

The c-Jun N-terminal kinases (JNKs) form a subgroup of mitogen-activated protein kinases that respond to metabolic and inflammatory stress signals. In obesity, excess nutrients and adipose tissue expansion trigger low-grade inflammation, characterised by increased pro-inflammatory cytokines and macrophage infiltration. Activation of JNK in adipose tissue, liver, skeletal muscle and the hypothalamus integrates these signals, leading to serine phosphorylation of key substrates such as insulin receptor substrate-1 (IRS-1). This modification impairs downstream insulin signalling, reducing glucose uptake and promoting systemic insulin resistance. Parallel JNK-dependent pathways influence pancreatic β-cell survival and function, aggravating hyperglycaemia. Animal models with tissue-specific JNK inhibition demonstrate protection against diet-induced obesity, improved insulin sensitivity and reduced hepatic gluconeogenesis. Conversely, constitutive JNK activation in specific neuronal populations drives hyperphagia, weight gain and leptin resistance. Recent efforts have explored selective JNK inhibitors and upstream modulators as potential therapeutics to restore metabolic homeostasis. By bridging inflammatory cues and metabolic control, JNK signalling remains central to the pathogenesis of obesity-associated insulin resistance and its comorbidities, offering actionable targets for intervention.

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JNK Signaling Pathways in Obesity and Insulin Resistance publication trend

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Technical terms

JNK: c-Jun N-terminal kinase, a stress-activated protein kinase that links inflammatory and metabolic signals to cellular responses.

IRS-1: Insulin receptor substrate-1, a docking protein that transmits signals from the activated insulin receptor to downstream effectors.

Serine phosphorylation: Addition of a phosphate group to a serine residue in a protein, often modulating its activity or interactions.

Insulin resistance: A pathological state in which cells fail to respond appropriately to insulin, leading to impaired glucose uptake and hyperglycaemia.

Adipocyte: A fat cell specialised in storing energy as lipid and secreting adipokines that regulate metabolism and inflammation.

References

1. Role of c-Jun N-terminal Kinase (JNK) in Obesity and Type 2 Diabetes. Cells (2020).
2. The c-Jun NH2-terminal Kinase Promotes Insulin Resistance during Association with Insulin Receptor Substrate-1 and Phosphorylation of Ser307 *. Journal of Biological Chemistry (2000).
3. Distinct Roles for JNK and IKK Activation in Agouti-Related Peptide Neurons in the Development of Obesity and Insulin Resistance. Cell Reports (2014).
4. Modulation of the JNK Pathway in Liver Affects Insulin Resistance Status*. Journal of Biological Chemistry (2004).
5. Impact of Conventional and Atypical MAPKs on the Development of Metabolic Diseases. Biomolecules (2020).
6. Selective Inactivation of c-Jun NH2-Terminal Kinase in Adipose Tissue Protects Against Diet-Induced Obesity and Improves Insulin Sensitivity in Both Liver and Skeletal Muscle in Mice. Diabetes (2011).