Despite their high degree of effectiveness in the management of psychiatric conditions, exposure to antipsychotic drugs, including olanzapine and risperidone, is frequently associated with substantial weight gain and the development of diabetes. Even before weight gain, a rapid rise in circulating leptin concentrations can be observed in most patients taking antipsychotic drugs. To date, the contribution of this hyperleptinemia to weight gain and metabolic deterioration has not been defined. Here, with an established mouse model that recapitulates antipsychotic drug–induced obesity and insulin resistance, we not only confirm that hyperleptinemia occurs before weight gain but also demonstrate that hyperleptinemia contributes directly to the development of obesity and associated metabolic disorders. By suppressing the rise in leptin through the use of a monoclonal leptin-neutralizing antibody, we effectively prevented weight gain, restored glucose tolerance, and preserved adipose tissue and liver function in antipsychotic drug–treated mice. Mechanistically, suppressing excess leptin resolved local tissue and systemic inflammation typically associated with antipsychotic drug treatment. We conclude that hyperleptinemia is a key contributor to antipsychotic drug–associated weight gain and metabolic deterioration. Leptin suppression may be an effective approach to reducing the undesirable side effects of antipsychotic drugs.

The pathogenesis of non-alcoholic fatty liver disease (NAFLD), the most prevalent chronic liver disease, is associated with zinc deficiency. Previous studies show zinc supplementation improves steatosis and glucose metabolism, but its therapeutic effects in patients with established NAFLD remain unclear. We developed an in vivo model to characterize the effects of zinc supplementation on high-fat diet (HFD) induced NAFLD and hypothesized that the established NAFLD would be attenuated by zinc supplementation. Male C57BL/6J mice were fed a control diet or HFD for 12 weeks. Mice were then further grouped into normal and zinc-supplemented diets for 8 additional weeks. Body composition and glucose tolerance were determined before and after zinc supplementation. At euthanasia, plasma and liver tissue were collected for characterization and downstream analysis. As expected, 12 weeks of HFD resulted in reduced glucose clearance and altered body composition. Eight weeks of subsequent zinc supplementation did not alter glucose handling, plasma transaminases, steatosis, or hepatic gene expression. Results from our model suggest 8-week zinc supplementation cannot reverse established NAFLD. The HFD may have caused NAFLD disease progression beyond rescue by an 8-week period of zinc supplementation. Future studies will address these limitations and provide insights into zinc as a therapeutic agent for established NAFLD.

Leptin, a hormone primarily secreted by adipocytes, regulates energy balance and systemic metabolism through its interaction with the leptin receptor (LEPR). Beyond these functions, leptin signaling has been implicated in the pathogenesis of tissue fibrosis. Here, we report the x-ray crystal structures of a leptin-neutralizing antibody (hLep3) in the unbound and leptin-bound states. The interaction of this antibody with leptin mimics the interaction of the LEPR with leptin, providing direct insights into the mechanism by which the antibody disrupts leptin signaling. We furthermore evaluate the therapeutic potential of neutralizing leptin with this antibody across distinct mouse models of fibrosis affecting the kidney, liver, lung, heart, and blood vessels. Leptin neutralization markedly inhibited fibrosis progression in all models. Mechanistically, suppression of leptin activity reduces pro-inflammatory and profibrotic processes, underscoring its therapeutic potential. These findings suggest that leptin signaling plays a vital role in tissue fibrosis and that treatment with a leptin-neutralizing antibody may be a promising therapeutic approach.

Proinflammatory signaling in adipocytes is essential for healthy adipose expansion, remodeling, and tissue integrity. We investigated the effects of targeting inflammation in either adipocytes or mammary gland epithelial cells, in the context of mammary tumor development, by locally expressing the antiinflammatory adenoviral RIDα/β protein complex in a cell type–specific manner. Suppression of adipocyte inflammation (RID ^ad mice) in a mammary tumor model driven by MMTV-PyMT (PyMT-RID ^ad mice) led to an elevated number of tumor-associated macrophages and upregulation of immunoregulatory molecules in the mammary fat pad. This was accompanied by metabolic dysfunction and abnormal mammary gland development. Importantly, this phenotype correlated with accelerated mammary tumor onset, enhanced growth, and lung metastasis. Tumors in PyMT-RID ^ad mice exhibited upregulated CD36 expression, suggesting enhanced fatty acid uptake. Conversely, suppression of inflammation in mammary gland epithelial cells by RIDα/β expression (RID ^MMTV mice) decelerated mammary tumor growth without affecting tumor onset or macrophage accumulation. These findings highlight the differential impact on tumor development exerted through the suppression of inflammatory signals in different cell types in the microenvironment. Our results underscore the role of the suppression of adipocyte inflammation leading to a tumor-friendly microenvironment, promoting mammary cancer progression. This study sheds light on the complex interplay between inflammation, specifically driven by the adipocyte, in breast cancer pathogenesis.

The prevalence of metabolic dysfunction-associated steatohepatitis (MASH) is rising worldwide. hFGF1^ΔHBS, a variant of human fibroblast growth factor 1 with three substitutions in its heparin-binding sites, was previously shown by our group to ameliorate fatty liver. However, hFGF1^ΔHBS also significantly modulates systemic metabolism, making it unclear whether its hepatic benefits arise from direct liver-specific actions. Additionally, its poor pharmacokinetic profile underscores the need for alternative delivery strategies. Here, we employed adeno-associated virus serotype 8 under the thyroxine-binding globulin promoter (AAV8-TBG) to achieve sustained, hepatocyte-specific expression of hFGF1^ΔHBS. In high-fat-, high-cholesterol-diet-fed apolipoprotein E knockout mice, liver-directed hFGF1^ΔHBS expression markedly reduced hepatic steatosis, inflammation, and fibrosis, independent of changes in body weight, blood glucose, insulin sensitivity, body composition, or circulating triglyceride and cholesterol levels. Mechanistically, hFGF1^ΔHBS gene transfer normalized fatty acid synthesis and suppressed fatty acid uptake by downregulation of stearoyl-CoA desaturase-1 and cluster of differentiation 36. Importantly, these therapeutic effects were achieved without inducing hepatic hyperproliferation, as evidenced by unchanged expression of proliferating cell nuclear antigen and antigen Kiel 67. Collectively, our findings demonstrate that hFGF1^ΔHBS exerts direct hepatoprotective effects and that AAV8-TBG-mediated liver-directed hFGF1^ΔHBS delivery represents a safe and effective strategy for treating MASH.

Fibroblast growth factor (FGF) 16 is critically involved in embryonic heart development, adult cardiac homeostasis, and potentially in metabolic regulation. Initially recognized for its cardiac-specific role during embryogenesis, recent studies demonstrate that FGF16 significantly mitigates pathological cardiac remodelling, such as fibrosis and hypertrophy, through competitive inhibition of FGF2-induced transforming growth factor-β1 signalling via FGF receptor 1c. Molecular investigations further indicate that FGF16 exerts cardioprotective effects primarily through activation of key intracellular pathways, including phosphoinositide 3-kinase/protein kinase B and protein kinase C, as well as regulation by transcription factors GATA binding protein 4, nuclear Factor kappa-light-chain-enhancer of activated B cells, and cardiac-specific homeobox/NK2 homeobox 5, and RNA methyltransferase-mediated N6-methyladenosine modifications. However, detailed mechanisms underlying receptor-specific interactions remain unclear. This review systematically summarizes the genomic organization, receptor selectivity, cardiac signalling mechanisms, and emerging metabolic roles of FGF16, critically evaluates the current evidence, identifies key research gaps, and highlights therapeutic potentials for cardiovascular and metabolic disorders.