Adipose tissue is an immunologically active organ that controls host physiology, partly through the release of mediators termed adipokines. In obesity, adipocytes and infiltrating leukocytes produce adipokines, which include the hormones adiponectin and leptin and cytokines such as tumour necrosis factor and IL-1β. These adipokines orchestrate immune responses that are collectively referred to as metabolic inflammation. Consequently, metabolic inflammation characterizes metabolic disorders and promotes distinct disease aspects, such as insulin resistance, metabolic dysfunction-associated liver disease and cardiovascular complications. In this unifying concept, adipokines participate in the immunological cross-talk that occurs between metabolically active organs in metabolic diseases, highlighting the fundamental role of adipokines in obesity and their potential for therapeutic intervention. Here, we summarize how adipokines shape metabolic inflammation in mice and humans, focusing on their contribution to metabolic disorders in the setting of obesity and discussing their value as therapeutic targets.

Interferon regulatory factor 3 (IRF3) is a transcription factor known primarily for its role in antiviral immunity via regulation of type I interferons (IFNs). Recent research has broadened its significance to encompass metabolic disorders, particularly obesity and diabetes. Obesity is characterized by chronic low-grade inflammation, insulin resistance, and metabolic dysfunction, all of which are increasingly found to be associated with immune signaling pathways. IRF3 has emerged as an important regulator in the development of obesity and type 2 diabetes (T2D), predominantly through its regulation of inflammatory cytokines production in various cells in adipose tissue. In obese individuals, IRF3 is activated in the adipocytes and adipose tissue macrophages, to promote the expression of inflammatory cytokines, thereby contributing to chronic inflammation and exacerbating insulin resistance. Moreover, IRF3 has been linked to mitochondrial dysfunction in hepatic disorders, further amplifying metabolic stress and imbalances associated with obesity. The growing evidence suggests that IRF3 is an important mediator in both immune and metabolic pathways, highlighting its potential as a target for the development of therapeutic interventions for obesity-related inflammation and metabolic dysfunction.

Psychotropic drugs such as antipsychotics improve symptoms of psychiatric disorders. However, they are associated with severe metabolic side effects that remodel energy balance, resulting in weight gain and increased food intake (hyperphagia). Here, we compare how antipsychotics and exogenous serotonin induce hyperphagia by remodeling energy balance. We find that the ability of serotonin and antipsychotics to remodel energy balance strictly depends on the serotonergic receptors SER-7 and SER-5, respectively. While both molecules induce hyperphagia, serotonin does so by increasing energy expenditure and reducing fat stores. In contrast, antipsychotics block the inhibitory effect of fat storage on feeding, thereby inducing hyperphagia and increasing fat stores. Thus, it is possible to manipulate energy balance to induce hyperphagia while either increasing or decreasing fat storage. Inactivation of the germline remodels energy balance similar to antipsychotic treatment, promoting hyperphagia while increasing fat storage. Consistent with overlapping mechanisms, antipsychotics are no longer able to remodel energy balance in both C. elegans and mice lacking an intact germline. Thus, our results uncouple overeating from fat storage and show that overeating can be induced by mechanisms that reduce or increase fat stores.

Olanzapine-induced fatty liver disease continues to pose vital therapeutic challenges in the treatment of psychiatric disorders. In addition, we observed that some patients were less prone to hepatic steatosis induced by olanzapine. Therefore, we aimed to investigate the role and the underlying mechanism of the intestinal flora in olanzapine-mediated hepatic side effects and explore the possible countermeasures. Our results showed that patients with different susceptibilities to olanzapine-induced fatty liver disease had different gut microbial diversity and composition. Furthermore, we performed fecal microbiota treatment (FMT), and confirmed that the gut microbiome of patients less prone to the fatty liver caused by olanzapine exhibited an alleviation against fatty liver disease in rats. In terms of mechanism, we revealed that the cross talk of leptin with the gut-short-chain fatty acid (SCFA)-liver axis play a critical role in olanzapine-related fatty degeneration in liver. These findings propose a promising strategy for overcoming the issues associated with olanzapine application and will hopefully inspire future in-depth research of fecal microbiota-based therapy in olanzapine-induced fatty liver disease.NEW & NOTEWORTHY Patients who were less inclined to have olanzapine-induced fatty liver had different gut microbiota profiles than did those in the susceptible cohort. Lachnospiraceae, Ruminococcaceae, Oscillospiraceae, Butyricicoccaceae, and Christensenellaceae were enriched in patients who were less prone to fatty liver disease caused by olanzapine. Fecal microbiota treatment (FMT) with these fecal samples promoted short-chain fatty acid (SCFA) production, which attenuated the circulating leptin and inhibited FASN and ACC1, thereby suppressing lipid synthesis in the liver, ultimately leading to alleviation of hepatic steatosis.

Gut microbial dysbiosis or altered gut microbial consortium, in schizophrenia suggests a pathogenic role through the gut-brain axis, influencing neuroinflammatory and neurotransmitter pathways critical to psychotic, affective, and cognitive symptoms. Paradoxically, conventional psychotropic interventions may exacerbate this dysbiosis, with antipsychotics, particularly olanzapine, demonstrating profound effects on microbial architecture through disruption of bacterial phyla ratios, diminished taxonomic diversity, and attenuated short-chain fatty acid synthesis. To address these challenges, novel therapeutic strategies targeting the gut microbiome, encompassing probiotic supplementation, prebiotic compounds, faecal microbiota transplantation, and rationalised co-pharmacotherapy, show promise in attenuating antipsychotic-induced metabolic disruptions while enhancing therapeutic efficacy. Harnessing such insights, precision medicine approaches promise to transform antipsychotic prescribing practices by identifying patients at risk of metabolic side effects based on their microbial profiles. This IUPHAR review collates the current literature landscape of the gut-brain axis and its intricate relationship with schizophrenia while advocating for integrating microbiome assessments and therapeutic management. Such a fundamental shift in proposing microbiome-informed psychotropic prescriptions to optimise therapeutic efficacy and reduce adverse metabolic impacts would align antipsychotic treatments with microbiome safety, prioritising 'gut-neutral' or gut-favourable drugs to safeguard long-term patient outcomes in schizophrenia therapy.

Psychotropic drug related weight gain is a common side-effect of significant concern to both clinicians and patients. Recent studies and treatment guidelines strongly support taking preventive and early treatment approaches to psychotropic drug-related weight gain (PDWG). Arguably the main pathway that PDWG occurs is via changes in eating behaviour leading to increased caloric intake.

Systematic reviews and meta-analyses have provided good data on the nature and prevalence of alterations in eating behaviour with psychotropic treatment including increased hunger, night eating and binge eating. These changes are unsurprisingly more prominent with agents like olanzapine and clozapine that have high propensity to cause weight gain.

Altered eating behaviour can serve as an earlier measure of the risk of weight gain and can be examined easily in clinical practice. Detecting these changes can enable earlier action in terms of switching treatments and starting pharmacological and nonpharmacological preventive strategies.

Although significant advances have been made in understanding the patho-physiology of psychiatric disorders (PDs), therapeutic advances have not been very convincing. While psychotropic medications can reduce classical symptoms in patients with PDs, their long-term use has been reported to induce or exaggerate various pre-existing metabolic abnormalities including diabetes, obesity and non-alcoholic fatty liver disease (NAFLD). The mechanism(s) underlying these metabolic abnormalities is not clear; however, lipid/fatty acid accumulation due to enhanced de novo lipogenesis (DNL) has been shown to reduce membrane fluidity, increase oxidative stress and inflammation leading to the development of the aforementioned metabolic abnormalities. Intriguingly, emerging evidence suggest that DNL dysregulation and fatty acid accumulation could be the major mechanisms associated with the development of obesity, diabetes and NAFLD after long-term treatment with psychotropic medications in patients with PDs. In support of this, several adjunctive drugs comprising of anti-oxidants and anti-inflammatory agents, that are used in treating PDs in combination with psychotropic medications, have been shown to reduce insulin resistance and development of NAFLD. In conclusion, the above evidence suggests that DNL could be a potential pathological factor associated with various metabolic abnormalities, and a new avenue for translational research and therapeutic drug designing in PDs.

Most antipsychotic drugs (APDs) induce hyperphagia and weight gain. However, the neural mechanisms are poorly understood, partly due to challenges replicating their metabolic effects in rodents. Here, we report a new mouse model that recapitulates overeating induced by clozapine, a widely prescribed APD. Our study shows that clozapine boosts food intake by inhibiting melanocortin 4 receptor (MC4R) expressing neurons in the paraventricular nucleus of the hypothalamus. Interestingly, neither clozapine nor risperidone, another commonly used APD, affects receptor-ligand binding or the canonical Gαs signaling of MC4R. Instead, they inhibit neuronal activity by enhancing the coupling between MC4R and Kir7.1, leading to the open state of the inwardly rectifying potassium channel. Deletion of Kir7.1 in Mc4r-Cre neurons prevents clozapine-induced weight gain, while treatment with a selective Kir7.1 blocker mitigates overeating in clozapine-fed mice. Our findings unveil a molecular pathway underlying the effect of APDs on feeding behavior and suggest its potential as a therapeutic target.

Antipsychotics are associated with severe metabolic side effects including insulin resistance; however, the mechanisms underlying this side effect are not fully understood. The skeletal muscle plays a critical role in insulin-stimulated glucose uptake, and changes in skeletal muscle DNA methylation by antipsychotics may play a role in the development of insulin resistance. A double-blind, placebo-controlled trial of olanzapine was performed in healthy volunteers. Twelve healthy volunteers were randomized to receive 10 mg/day of olanzapine for 7 days. Participants underwent skeletal muscle biopsies to analyze DNA methylation changes using a candidate gene approach for the insulin signaling pathway. Ninety-seven methylation sites were statistically significant (false discovery rate < 0.05 and beta difference between the groups of ≥10%). Fifty-five sites had increased methylation in the skeletal muscle of olanzapine-treated participants while 42 were decreased. The largest methylation change occurred at a site in the Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-Alpha (PPARGC1A) gene, which had 52% lower methylation in the olanzapine group. Antipsychotic treatment in healthy volunteers causes significant changes in skeletal muscle DNA methylation in the insulin signaling pathway. Future work will need to expand on these findings with expression analyses.