Attack of the kinases: JNK signaling in metabolism.

Dysregulation of JNK signaling has been increasingly implicated in the association between obesity and metabolic disease in humans ( 73 – 76 ). Obesity in humans is characterized by chronic metabolic stress, including elevated circulating free fatty acids, pro-inflammatory cytokines and (ER) stress, all of which converge on stress-activated kinases such as JNK ( 73 – 76 ). In this context, JNK acts as an integrator of metabolic and inflammatory cues, contributing to inhibitory phosphorylation of IRS, β-cell dysfunction and dysregulated glucose homeostasis that favor the development of type 2 diabetes ( 73 – 76 ). Transcriptomic and proteomic analyses indicate that JNK1 and JNK2 are the predominant isoforms activated in inflamed human adipose tissue and liver, whereas JNK3 expression is largely restricted to brain and pancreatic tissues ( 76 , 147 , 148 ). Although most human datasets do not resolve isoform-specific signaling in detail, they nevertheless support a preferential involvement of JNK1/2 in peripheral metabolic inflammation ( 73 – 76 , 149 ). Direct human data reinforce the translational relevance of these pathways. In adipose tissue biopsies from individuals with obesity, increased ER-stress markers and enhanced JNK phosphorylation have been reported, and both ER-stress signatures and JNK activation decline after weight-loss interventions, in parallel with improvements in mitochondrial function, insulin sensitivity and systemic metabolic status ( 150 ). These observations highlight the plasticity of stress-activated kinase signaling in human tissues and support the view of JNK as a modifiable node in metabolic disease. Consistent with these findings, several studies emphasize a role for JNK signaling in human adipose tissue inflammation and systemic insulin resistance. JNK activation is frequently detected as part of the inflammatory kinome upregulated in obesity and is associated with a shift of adipose tissue toward a pro-inflammatory, cytokine-rich phenotype that interferes with insulin signaling in adipocytes and infiltrating immune cells ( 151 ). Inflammatory mediators derived from obese adipose tissue can, in turn, activate JNK signaling in multiple metabolic organs, establishing a feed-forward loop that reinforces insulin resistance ( 152 , 153 ). Beyond adipose tissue, JNK dysregulation is also implicated in obesity-associated vascular and endothelial abnormalities ( 154 – 156 ). A wingless-type MMTV integration site family, member 5A (WNT5A)-JNK axis has been identified in human vascular tissues, where increased WNT5A/JNK signaling associates with endothelial insulin resistance, reduced nitric-oxide bioavailability and impaired vasodilator responses in arterioles from obese or diabetic subjects ( 155 ). Pharmacological inhibition of WNT5A or JNK in ex vivo human vessels restores endothelial insulin signaling and nitric-oxide production, linking JNK activation to vascular dysfunction that may contribute to increased cardiovascular risk in obesity and type 2 diabetes ( 155 ). In addition, to metabolic-induced vascular impairment, it has been also shown that JNK is involved in the inflammatory signaling of the vascular endothelium ( 156 ). So, unidirectional shear stress suppresses endothelial inflammation by inhibiting a yes‑associated protein/transcriptional co‑activator with PDZ‑binding motif (YAP/TAZ)-JNK signaling cascade. Protective flow inactivates YAP/TAZ, which reduces JNK activation and downstream pro‑inflammatory gene expression in endothelial cells. Conversely, disturbed flow activates YAP/TAZ and JNK, promoting vascular inflammation and atherosclerosis, while YAP/TAZ inhibition blunts JNK signaling and lesion formation ( 156 ). Collectively, current evidence supports JNK dysregulation as an important mechanistic link between obesity and metabolic pathology in humans. JNK acts as a stress-responsive signaling integrator that translates nutrient excess and inflammation into impaired insulin action, adipose tissue dysfunction, endothelial abnormalities and systemic metabolic dysregulation ( 73 – 76 , 149 ). These effects arise through both direct phosphorylation of metabolic signaling components and interactions with inflammatory and ER stress pathways ( 73 – 76 , 149 ). Future studies should prioritize defining tissue and isoform specific functions of JNK signaling in human metabolic disease and rigorously evaluating the safety and efficacy of JNK directed interventions.

Among the three isoforms of JNK, JNK1 is the most abundant in the CNS and is expressed in both neurons and glial cells ( 35 ). Its expression localizes to axonal and dendritic compartments and plays essential roles in regulating neuronal morphology, cytoskeletal dynamics, and synaptic plasticity ( 35 , 58 ). These structural and signaling functions extend beyond neuronal development, portraying implications of JNK1 in broader neuroendocrine processes, particularly in energy balance and metabolic regulation ( 35 ). Most of the available evidence on the hypothalamic role of JNK derives from studies employing pharmacological inhibition and genetically modified mouse models ( Table 1 ). Collectively, genetic and pharmacological manipulations of central JNK signaling reveal isoform- and circuit-specific control of feeding behavior, neuroendocrine function, and peripheral metabolic regulation, providing a conceptual framework to understand how hypothalamic JNK pathways drive systemic metabolic outcomes. The central relevance of JNK1 in metabolic physiology was first elucidated through studies employing Nestin-Cre-mediated deletion of Jnk1 gene, which targets neurons and astrocytes during development. It was demonstrated that neuronal JNK1-deficient mice were protected from HFD-induced obesity, insulin resistance, and glucose intolerance ( 61 , 119 , 129 ). These mice displayed enhanced insulin signaling in the hypothalamus and peripheral tissues, reduced hepatic steatosis and increased energy expenditure ( 61 , 119 , 129 ). Moreover, neuroendocrine changes included elevated circulating levels of triiodothyronine (T3) and thyroxine (T4), as well as increased expression of thyrotropin-releasing hormone (TRH) in the hypothalamus, suggesting that JNK1 modulates the hypothalamic-pituitary-thyroid (HPT) axis. However, initial observations regarding body weight failed to show significant differences between KO and control groups, prompting further investigation into the cell type-specific functions of JNK1. This disparity was addressed in a study wherein they generated mice with agouti-related peptide (AgRP)-specific JNK1 overexpression ( 123 ). These mice exhibited leptin resistance, hyperphagia, and pronounced susceptibility to diet-induced obesity ( 123 ). This work confirmed that JNK1 impairs leptin signaling in hypothalamic orexigenic neurons and plays a direct mechanistic role in promoting positive energy balance under obesogenic conditions. In addition to its role in leptin resistance, JNK1 interacts with the tumor suppressor p53 to influence energy homeostasis ( 122 ). It was demonstrated that mice lacking p53 specifically in AgRP neurons were more prone to diet-induced obesity and showed elevated levels of phosphorylated JNK (pJNK) in the VMH. Notably, central pharmacological inhibition of JNK with SP600125 was able to reverse this phenotype, thus highlighting the synergistic contribution of JNK1 and p53 in regulating hypothalamic circuits that mediate systemic energy metabolism ( 122 ). Further significant and diverse aspects on the neuroendocrine roles of JNK1, it has been recently identified this kinase as an essential mediator of thyroid hormone signaling in the CNS. In hyperthyroid rats, increased pJNK1 levels in the VMH correlated with hepatic lipid accumulation via activation of the PSNS ( 50 , 98 ). Additionally, central administration of T3 failed to induce hepatic lipogenesis in JNK1-deficient mice, demonstrating that JNK1 is required for transducing thyroid hormone signaling from the hypothalamus to the liver ( 98 ). Intriguingly, overexpression of AMP-activated protein kinase (AMPK) in the VMH inhibited T3-induced JNK1 activation, suggesting that AMPK negatively regulates this signaling pathway and may act as an vital upstream modulator of JNK1-mediated lipid metabolism ( 50 ). More recently, the function of JNK1 in hypothalamic subcircuits by examining its roles in steroidogenic factor 1 (SF1) expressing neurons of the VMH was also elucidated. JNK1 in SF1 neurons is indispensable for central parasympathetic output to hepatic lipogenesis, thereby supplying lipid-derived fuel to BAT during cold exposure and thyroid-hormone stimulation. Loss of JNK1 in SF1 neurons decouples these autonomic branches, impairing thermogenic adaptation and energy homeostasis ( 98 ). These mice were protected from hepatic steatosis and showed improved glucose tolerance, despite normal BAT thermogenesis and increased adiposity under HFD feeding ( 98 ). These beneficial effects occurred without alterations in food intake or basal metabolic rate, indicating that JNK1 in SF1 neurons plays a specific role in the central regulation of hepatic lipid metabolism, independent of effects on energy expenditure or thermogenesis even during thyroid hormone stimulation ( Figure 4 ). Strikingly, this phenotype uncoupled the sympathetic (SNS) and PSNS outputs of the VMH. While central JNK1 deficiency improved liver metabolism, it impaired cold-induced thermogenesis and led to increased mortality under thermal stress, likely due to defective mobilization of lipid-derived fuels ( 98 ). These findings suggest that JNK1 in SF1 neurons is indispensable for coordinative adaptive thermogenic responses and for maintaining the balance between hepatic lipid control and BAT-mediated heat production ( 98 ) ( Figure 4 ). This finding reinforces the mechanistic connection previously described between AMPK, endoplasmic reticulum stress, and JNK1 signaling in thyroid hormone-induced hepatic lipogenesis, positioning JNK1 SF1 neurons as a pivotal relay between the HPT axis and liver lipid homeostasis ( 50 , 98 ). Moreover, this evidence reveals a functional dichotomy in JNK1 signaling between central and peripheral tissues. Wherein peripheral JNK1 deficiency has been widely associated with increased hepatic lipid accumulation and insulin resistance ( 92 ), central deletion of JNK1, particularly in SF1 neurons, produces the opposite phenotype ( 98 ). These opposing roles again highlight that the effects of JNK1 are context- and cell type-dependent, governed by distinct upstream regulators and downstream effectors in each tissue. Finally, very recent evidence has linked the hypothalamic actions of JNK1 to the effects of the antipsychotic drug olanzapine. Specifically, activation of the hypothalamic JNK1-hepatic fatty acid synthase (FAS) axis mediates a metabolic adaptation in male mice treated with olanzapine via intraperitoneal injection, protecting them against hepatic steatosis by rewiring liver metabolism ( 130 ). Additionally, inhibiting PTP1B enhances these protective effects, further preventing fat accumulation within the liver ( 130 ). This research shows the significance of central nervous system-liver communication in drug-induced metabolic dysfunction and highlights JNK1 and PTP1B modulation as promising strategies to counteract olanzapine-related hepatic complications. Taken together, these findings indicate that hypothalamic JNK1 is one of the master regulators of energy balance in the CNS, with divergent actions depending on neuronal subtype and anatomical location. Therapeutic strategies aimed at modulating JNK1 must therefore account for its tissue-specific roles to avoid unintended metabolic consequences.

Chronic low-grade inflammation is now recognized as a hallmark of obesity and considered as a major driver for its associated metabolic complications ( 4 , 31 , 35 , 52 ). Central to this inflammatory upheaval are the JNK stress-responsive kinases that modulate gene expression by phosphorylating c-Jun, thereby activating the activator protein-1 (AP-1) transcription factor complex and enhancing the transcription of proinflammatory cytokines ( 53 – 55 ) ( Figure 2 ). JNKs are part of the mitogen-activated protein kinase (MAPK) family and are activated by a variety of environmental and intracellular stressors including reactive oxygen species (ROS), ultraviolet radiation, endoplasmic reticulum (ER) stress, and proinflammatory cytokines ( Figure 2 ) ( 54 – 57 ). The family comprises three isoforms: JNK1 (Mapk8), JNK2 (Mapk9), and JNK3 (Mapk10). JNK1 and JNK2 are ubiquitously expressed, while JNK3 is restricted to specific tissues such as the brain, heart, and pancreatic β-cells ( 55 , 58 – 60 ). Their functional diversity is further augmented by alternative splicing, generating at least 10 isoforms with unique regulatory capacities ( 53 , 55 , 61 ). The activation of JNK involves a highly ordered kinase cascade starting with MAPK kinase kinases (MAP3Ks), followed by MAPK kinases (MKK4 and MKK7), culminating in the phosphorylation of this protein ( 54 , 55 , 57 , 60 ). Distinct MAP3Ks are engaged depending on the nature of the stimulus ( 57 ). For example, transforming growth factor-β activated kinase 1 (TAK1) is essential for JNK activation by tumor necrosis factor alpha (TNF-α), tumor necrosis factor beta (TGF-β) and interleukin-1 beta (IL-1β), and participates in toll-like receptor (TLR) signaling ( 57 , 62 , 63 ). Similarly, MEKK3 mediates JNK activation in response to TLR8 stimulation, while mixed lineage kinase 3 (MLK3) and tumor progression locus 2 (TPL2) have been shown to mediate TNF-induced JNK activation in fibroblasts and macrophages ( 57 , 62 , 64 ). Nevertheless, exhibiting overlapping and context-dependent functions by various MAP3K’s, their stimulus-specific signaling mechanisms remain incompletely resolved ( 57 , 62 ). Termination of JNK signaling is tightly regulated to prevent prolonged activation that could promote inflammatory, metabolic, or apoptotic dysfunction. A primary mechanism of inactivation is mediated by dual-specificity phosphatases (DUSPs), which dephosphorylate the threonine and tyrosine residues within the TPY activation motif ( 65 ). DUSP1/MKP-1 is the best-characterized negative regulator of JNK; its deletion leads to sustained JNK phosphorylation, whereas its induction by stress-responsive transcription factors, including c-Jun, establishes a negative feedback loop that limits pathway output ( 56 , 65 , 66 ). DUSP1 activity is also modulated by redox status, and its oxidative destabilization can prolong JNK activation during inflammatory and metabolic stress. Additional DUSPs contribute to context-specific JNK regulation. DUSP2, traditionally considered to be ERK-selective, can also bind and modulate JNK1, wherein DUSP2-deficient models showed altered JNK phosphorylation kinetics in immune setting ( 65 – 67 ). DUSP8 shows strong preference for JNK isoforms and participates in reciprocal feedback regulation, as JNK-dependent phosphorylation attenuates its activity ( 65 , 66 , 68 , 69 ). Other phosphatases, including DUSP3, DUSP6, DUSP7, DUSP12, DUSP13B and DUSP18, also constrain JNK signaling in a stimulus- or cell-specific manner ( 65 , 66 ). Collectively, DUSPs establish a multilayered regulatory system that shapes both magnitude and duration of JNK signaling across physiological and pathophysiological contexts. Scaffold proteins provide an additional layer of regulation by organizing kinase modules and directing signal flow with spatial precision. JNK-interacting protein 1 (JIP1) a scaffold protein tethers JNK to its upstream kinases and substrates ( 36 ), thereby coordinating signal propagation. JIP1-deficient mice exhibit impaired JNK activation in response to fasting, high-fat diet (HFD) feeding, and neuronal injury ( 58 , 61 , 70 ). JIP1 also interacts with the Notch and Akt pathways, suggesting its broader roles in cellular homeostasis and differentiation. In neurons, JIP1 and JIP3 associate with motor proteins such as kinesin-I and the dynactin complex to mediate axonal transport of JNK signaling complexes ( 58 , 70 ). This axonal transport mediated together by scaffold proteins and motor proteins is required for retrograde injury signaling and may also influence nutrient sensing and energy homeostasis in hypothalamic neurons ( 58 , 61 ).

Although JNK1 has been extensively studied in central metabolic circuits, the role of JNK2 in the CNS is considerably less defined. Nonetheless, recent findings suggest that JNK2 may also have major contributions to neuroendocrine regulation. Studies using combined deletion of JNK1 and JNK2 in the brain and pituitary have shown resistance to diet-induced obesity, enhanced energy expenditure, and elevated expression DIO2 in the anterior pituitary ( 124 ). These effects occurred even though TRH expression in the hypothalamus was reduced, indicating that the normal communication between the brain, pituitary, and thyroid was disrupted. This suggests that JNK2 helps to control how the pituitary activates thyroid hormones and how the brain regulates the body’s energy balance ( 124 ). Furthermore, JNK2 is activated in the hypothalamus under nutrient excess conditions, alongside JNK1 and JNK3, indicating its involvement metabolic mediated stress response in the brain. Despite, no neuron-specific or isoform-selective ablation of JNK2 alone has not conducted yet, the data point to a potential role in modulating leptin or insulin signaling, HPT axis feedback and ER stress pathways ( 31 , 35 , 50 , 55 , 57 ). Therefore, future studies using cell type-specific deletion of Mapk9 in SF1, POMC, AgRP, astrocyte or tanycyte populations are required to clarify the extent of JNK2’s contribution to central metabolic regulation.

JNK signaling represents a central node integrating inflammatory, hormonal, and nutritional cues that regulate systemic metabolism ( 35 , 73 – 76 ), yet several critical questions remain unanswered to further guide future research. These include: i) the precise, cell type-specific functions of JNK isoforms in hypothalamic neurons and glial cells; ii) the differential interactions of JNK isoforms with hormonal axes, such as the thyroid axis, the adrenal axis and the gonadal axis and iii) whether JNK3 can be selectively targeted for neuroprotection without disrupting metabolic control. Additional landscape includes iv) the circuit-level interactions between JNK isoforms in context with nutrient sensors such as AMPK and mTOR. Addressing these questions will be essential to refine our understanding of JNK as a central regulator of energy balance and its isoform-specific roles across central and peripheral tissues. Ultimately, elucidating the precise interactions of JNK within defined hypothalamic and metabolic circuits will be critical for translating mechanistic insights into safe and effective therapies for obesity and related metabolic disorders.

There is compelling preclinical evidence implicating JNK signaling in both metabolic and neurodegenerative disorders, with much of our current understanding derived from murine models employing global or region-specific genetic manipulations ( 35 , 59 , 104 , 131 ). These models have been, and continue to be, indispensable for dissecting the molecular mechanisms of underlying JNK function. However, genetic KO approaches can sometimes trigger compensatory activation of other MAPK pathways, such as p38 or ERK, which may complicate the interpretation of JNK-specific effects ( 35 , 55 , 57 ). Future studies could benefit from incorporating chemogenetic and optogenetic strategies to achieve temporal and cell type-specific control of JNK1 activity, thereby allowing a more precise characterization of these pathways and their dynamics under physiological and pathological conditions. Although rodent models provide a robust and highly tractable platform to investigate JNK signaling in vivo, translating these findings to humans requires awareness of certain interspecies differences in brain architecture, endocrine feedback mechanisms, and immune-metabolic communications. For example, human neurons exhibit distinct JNK isoform expression patterns, kinase substrate interactions, and timelines for developmental plasticity and metabolic programming compared to rodents ( 21 , 73 , 74 ). Rather than diminishing the value of murine research, these nuances highlight the importance of complementing rodent data with human-based and comparative approaches to strengthen translational impact. Although studies in non-human primates (NHPs) are relatively scarce, available evidence indicates activation of hypothalamic JNK is associated with central leptin resistance and increased neuroinflammation, echoing the results from rodent models. Nevertheless, primate-specific traits, such as longer lifespans, unique reproductive cycles, and greater metabolic flexibility, introduce additional regulatory layers that may influence JNK signaling outcomes. Well-structured experiments in species such as macaques or baboons could help in evaluating the efficacy and safety of JNK inhibitors in a physiological context closer to that of humans, while rodent models remain essential for mechanistic exploration and early-stage intervention testing. Advances in stem cell biology now enable the generation of human iPSC-derived hypothalamic organoids containing functional orexigenic and anorexigenic neurons, glial markers, and even partial vascularization when matured in vitro or in vivo. Hypothalamic organoids, postmortem brain tissue, and in vivo neuroimaging will also be considered as key in refining translational relevance ( 35 , 133 , 134 ). The interplay between JNK1 and other metabolic regulators, such as AMPK, mammalian target of rapamycin complex (mTORC1), phosphatidylinositol 3-kinase PI3K/Akt, ER stress signaling and sirtuin 1 (SIRT1), remains incompletely understood ( 9 , 13 , 35 , 50 , 98 , 120 , 121 , 135 ). AMPK-JNK interactions, for instance, are known to influence ER stress during thyroid hormone signaling ( 50 , 98 ), but their roles in fasting, neuroendocrine regulation, circadian rhythms, and physical activity warrants further investigation. Mapping these relationships at the neural circuit level in both rodent and human systems will be essential in understanding how JNK integrates into broader metabolic networks. Sex differences is also an underexplored dimension in preclinical research in the perspective of the role of JNK in metabolic wellbeing. Although most studies use male rodents, accumulating evidence shows that neuroendocrine and metabolic responses to hypothalamic perturbations differ by sex ( 6 , 136 , 137 ). Female animals exhibit cyclical gonadal and steroid fluctuations that are known to affect hypothalamic plasticity, glial activity and energy expenditure, which are factors likely to be influenced by JNK signaling ( 98 ). Investigating how these hormonal cycles modulate JNK1 activity could uncover sex-specific mechanisms and therapeutic opportunities. Hitherto, no JNK-targeted therapies have received clinical approval. Most compounds remain in early developmental phases and are impacted from factors such as isoform redundancy, poor pharmacokinetics, and off-target effects. For example, pan-JNK inhibitors have demonstrated efficacy in preclinical models by reducing inflammation and improving insulin sensitivity ( 108 , 127 , 138 ). However, their lack of selectivity raises concerns about potential interference with JNK3-mediated neuroendocrine and cognitive functions ( 35 , 104 , 131 ). Examples include SP600125, a broad-spectrum JNK1/2/3 inhibitor limited by low specificity and systemic toxicity, and AS602801 (PGL 5001 or CC 930), which reached Phase II trials for idiopathic pulmonary fibrosis and endometriosis, but was further discontinued due to limited efficacy and safety concerns ( 108 , 138 ). Tanzisertib (CC 90001 or BMS 986360) advanced to clinical testing for fibrotic disorders and was generally well tolerated yet failed to demonstrate sufficient efficacy for continued development ( 139 ). Advances in structural biology, molecular docking, and kinase-substrate interaction mapping are enabling the development of more selective, isoform-specific inhibitors and allosteric modulators ( 139 – 141 ). These precision-based approaches aim, for example, to fine-tune JNK1/2 signaling in peripheral tissues while preserving JNK3 activity in the brain. Selective JNK3 inhibitors are also being actively investigated for neuroprotection in models of Parkinson’s and Alzheimer’s disease. Additional strategies also include targeting upstream kinases (e.g., MKK4/7), scaffold proteins (e.g., JIP1), and downstream transcriptional effectors (e.g., c-Jun, ATF2, FOXO1) to achieve greater specificity ( 108 , 141 ). One promising example is the peptide D-JNKI 1 (XG 102), which disrupts JNK-JIP1 interactions ( 140 , 142 ). In JIP1-deficient mice, this intervention attenuates diet-induced obesity and insulin resistance, highlighting JNK-JIP signaling as a therapeutic axis ( 140 , 142 ). D-JNKI 1 has demonstrated safety in human trials for postoperative ocular inflammation and therapeutic efficacy in animal models of colitis and CNS disorders ( 126 , 132 ). Finally, besides small-molecule and peptide-based strategies, recent studies have highlighted the potential role of small extracellular vesicles (sEVs) as a platform for targeted brain delivery. Thus, systemically administered sEVs can reach VMH SF1 neurons and modulate hypothalamic AMPKα1 activity, promoting BAT-mediated thermogenesis and weight reduction in obese models ( 143 – 145 ). Alternative promoter-derived strategies have also allowed to target AMPKα2 in cortical neurons for the treatment of ischemic stroke ( 146 ). These findings illustrate a feasible and highly specific approach for delivering molecular modulators to defined brain populations. Implementing such approaches will provide a basis for exploring similar strategies to modulate JNK1 signaling in the CNS while minimizing off-target effects in peripheral tissues.

Beyond metabolic sensing, the hypothalamus also functions as an immunometabolic interface ( 21 ). Circulating proinflammatory cytokines, such as interleukin 1β (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α), access the hypothalamus via humoral entry at the median eminence (ME), bypassing the blood-brain barrier (BBB), activating neural relays through vagal afferents and by binding to specific cytokine receptors in the endothelium comprising the BBB ( 21 , 29 – 39 ). Once they traverse the BBB, these cytokines activate intracellular inflammatory signaling cascades, including c-Jun N-terminal kinase (JNK), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), p38 MAPK, and extracellular signal-regulated kinase (ERK) pathways ( 29 – 39 ). Through these mechanisms, the hypothalamus coordinates adaptive responses to systemic inflammation, such as fever induction, anorexia, autonomic adjustments, and modulation of hepatic glucose and lipid metabolism ( 21 , 29 – 39 ). While these responses are beneficial during acute immune activation, chronic nutrient excess, particularly high-fat diet (HFD) feeding, drives persistent engagement of these pathways in the hypothalamus. This inflammatory state is characterized by microglial activation, astrogliosis, endoplasmic reticulum stress (ER), leading to local cytokine production and amplification of neuroinflammation ( 29 – 39 ). Lipid-induced ER stress has emerged as a critical mechanistic link between chronic nutrient overload and hypothalamic inflammation ( 40 – 46 ). Saturated fatty acids like palmitic acid abundant in HFD promote the synthesis of sphingolipids, particularly ceramides, in hypothalamic neurons and glial cells, imposing a lipotoxic burden on ER homeostasis. Long chain ceramides, such as C16:0 ceramide, in hypothalamic neurons promote ER and mitochondrial stress, disrupting central leptin and insulin signaling, and impairs glucose homeostasis under conditions of dietary lipid excess ( 40 – 43 , 46 – 48 ). This activates the unfolded protein response (UPR) ( 45 , 46 , 49 ). Corroborating these findings, experimental increases in hypothalamic ceramide robustly engaged these canonical UPR sensors, resulting in cellular dysfunction and impaired metabolic regulation ( 46 , 50 ). Genetic or pharmacological alleviation of ER stress could also markedly attenuate ceramide-induced hypothalamic inflammation ( 46 , 50 , 51 ). Ceramide-induced endoplasmic reticulum stress in the MBH upregulates the ER-resident chaperone GRP78/BiP, leading to attenuation of ER stress signaling. This restoration of ER homeostasis normalizes sympathetic outflow to BAT, thereby increasing thermogenic activity and improving whole-body energy balance ( 46 , 50 , 51 ).

In contrast to JNK1, accumulating evidence supports a primarily homeostatic role for JNK3 in the hypothalamus, acting to restrain hyperphagia and preserve energy balance under metabolic stress. As previously mentioned, the expression of JNK3 is almost completely restricted to the CNS, with particularly high levels in the hippocampus, cortex, and hypothalamus; for this reason, it is the most neuron-specific isoform of the MAPK family ( 35 , 58 , 59 , 131 ). Initially, JNK3 was primarily studied in the context of neuronal apoptosis, where its activation is closely associated with oxidative stress, excitotoxicity, and ischemic injury ( 58 , 59 , 131 ). These properties have made JNK3 a candidate therapeutic target in the context of neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease ( 131 , 132 ). However, more recent studies have expanded the functional repertoire of JNK3, revealing its involvement in hypothalamic regulation of energy homeostasis, feeding behavior, and metabolic adaptation. One of the most compelling roles of JNK3 in the hypothalamus is the relation to cellular stress brought by nutritional overload, particularly under HFD conditions. Several studies have demonstrated that HFD feeding results in the activation of JNK3 in specific hypothalamic neuronal populations, indicating its contribution in the central control of metabolism ( 35 , 104 , 123 ). Experimental models involving global JNK3 KO and conditional deletion in hypothalamic neurons have yielded interesting insights. For instance, whole-body deletion of JNK3 ( 104 ) and selective deletion of JNK3 in agouti-related peptide (AgRP) neurons ( 104 ) induce hyperphagia and increased adiposity on HFD, pointing its key role in appetite regulation. Mechanistically, JNK3 seems to function downstream of leptin signaling in AgRP neurons. That effect may represent as a compensatory mechanism to counteract the hyperphagic drive induced by HFD, helping to preserve energy balance under obesogenic conditions Therefore, JNK3 underscores a striking isoform-specific divergence in JNK’s function within the hypothalamus ( 35 , 104 , 123 ). This functional dichotomy between JNK1 and JNK3 highlights the complexity of MAPK signaling in hypothalamic networks and suggests that JNK3 may serve as a homeostatic regulator, fine-tuning the neural circuits that govern feeding behavior and energy balance in response to environmental cues.