Obesity has recently been defined as a chronic low-grade inflammatory disease. Obesity-induced inflammation of adipose tissue (AT) is an essential trigger for insulin resistance (IR) and related metabolic diseases. Although the underlying molecular basis of this inflammation has not been fully identified, there is consensus that the recruited and activated macrophages in AT are the most important culprits of AT chronic inflammation. Adipose tissue macrophages (ATMs) are highly plastic and could be polarized from an anti-inflammatory M2 to proinflammatory M1 phenotypes on stimulation by microenvironmental signals from obese AT. Many efforts have been made to elucidate the molecular signaling pathways of macrophage polarization; however, the upstream drivers governing and activating macrophage polarization have rarely been summarized, particularly regulatory messages from the AT microenvironment. In addition to adipocytes, the AT bed also contains a variety of immune cells, stem cells, as well as vascular, neural, and lymphatic tissues throughout, which together orchestrate the AT microenvironment. Here, we summarize how the aforesaid neighbors of ATMs in the AT microenvironment send messages to ATMs and thus regulate its phenotype during obesity. Deciphering the biology and polarization of ATMs in the obese environment is expected to provide a precise immunotherapy for adipose inflammation and obesity-related metabolic diseases.

Zinc-α2-glycoprotein (ZAG) is a recently novel lipolytic adipokine implicated in regulation of glucose and lipid metabolism in many metabolic disorders. In vitro and animal studies suggest that thyroid hormones (TH) up-regulates ZAG production in hepatocytes. However, there is no data evaluating the possible relationship between ZAG and TH in a human model of hyperthyroidism. The objective of the present study is to assess the association of serum ZAG levels with TH and lipid profile in patients with hyperthyroidism before and after methimazole treatment. A total of 120 newly diagnosed overt hyperthyroidism and 122 healthy control subjects were recruited. Of them, 39 hyperthyroidism patients were assigned to receive methimazole treatment as follow-up study for 2 months. The clinical consequence showed that serum ZAG levels were elevated in patients with hyperthyroidism (P < 0.01). Adjust for age, gender and BMI, serum ZAG levels were positively related with serum free T3 (FT3), free T4 (FT4) levels and negatively correlated with serum total cholesterol (TC), low density lipoprotein cholesterol (LDLC) levels in hyperthyroidism subjects (all P < 0.01). After methimazole treatment, serum ZAG levels were decreased and the decline was associated with decreased FT3, FT4 and increased TC levels (all P < 0.001). We conclude that ZAG may be involved in the pathogenesis of lipid metabolism disorder in patients with hyperthyroidism. ChiCTR-ROC-17012943 . Registered 11 October 2017, retrospectively registered.

Purpose: Growth differentiation factor 3 (GDF3), a TGFβ superfamily cytokine, has been linked to visceral adipose proliferation and adiposity in animal studies. However, the relationship between circulating GDF3 levels and visceral adiposity in humans remains unclear. This study aimed to assess the potential of serum GDF3 as a biomarker for visceral obesity. Patients and Methods: This study comprised a cross-sectional component and an embedded self-controlled interventional component. A total of 282 adults aged 18– 65 years were enrolled, including 162 individuals with visceral obesity and 120 without visceral obesity. Visceral obesity was defined as a visceral fat area (VFA) ≥ 100 cm². In addition, 23 participants with visceral obesity completed a 12-week semaglutide weight-loss intervention with follow-up assessments. Serum levels of GDF3, IL-6, TNF-α and MCP-1 were measured by enzyme-linked immunosorbent assay. Correlation analyses, multivariable logistic regression, linear regression, and exploratory mediation analyses were performed to evaluate the associations of serum GDF3 with visceral obesity and related metabolic-inflammatory parameters. Results: Serum GDF3 levels were significantly higher in adults with visceral obesity than in those without visceral obesity (P < 0.001). Multivariable logistic regression showed that serum GDF3 was independently associated with visceral obesity. Moreover, after 12 weeks of semaglutide intervention, reductions in visceral fat were positively correlated with reduction in serum GDF3 levels (r = 0.437). Linear regression analyses indicated that, in addition to VFA, HOMA-IR, TNF-α, and MCP-1 were independently associated with serum GDF3 levels. Mediation analyses suggested that serum GDF3 may partially mediate the associations of VFA with MCP-1 and HOMA-IR. Conclusion: GDF3 may be a circulating biomarker of visceral obesity and a potential mediator linking visceral fat accumulation to related insulin resistance and inflammatory disturbances.

Background and Aims: Liver fibrosis is the principal histological determinant of mortality in metabolic dysfunction–associated steatohepatitis (MASH), yet the mechanisms driving progression from steatosis to fibrosis remain incompletely defined and effective antifibrotic therapies are limited. Although hepatocyte-derived exosomes under lipotoxic stress promote HSC activation, the pathogenic protein cargos remain undefined. This study sought to identify lipotoxicity-induced hepatocyte-derived exosomal proteins that drive MASH fibrogenesis and to define their mechanistic and therapeutic relevance. Approach and Results: Proteomic analysis of hepatocyte-derived exosomes from murine MASH livers and lipotoxic hepatocyte cultures identified N-acetyltransferase 10 (NAT10) as a stress-enriched exosomal cargo. zinc finger DHHC-type palmitoyltransferase 23 (ZDHHC23)-mediated palmitoylation promoted NAT10 nuclear export and exosomal loading. Functional studies demonstrated that exosomal NAT10 drove fibrogenic signaling in HSCs by enhancing N4-acetylcytidine (ac4C) RNA acetylation and stabilizing Ddr2 mRNA. Hepatocyte-specific Nat10 deletion or administration of NAT10-deficient exosomes attenuated liver fibrosis, whereas hepatocyte Nat10 overexpression exacerbated fibrogenesis in an exosome-dependent manner. In human liver samples, increased NAT10 expression and elevated extranuclear-to-nuclear ratio correlated with fibrosis severity. Finally, hepatocyte-targeted N-acetylgalactosamine-si Nat10 significantly ameliorated fibrosis in murine MASH models. Conclusions: This study links aberrant nuclear protein localization to subsequent exosome-mediated fibrogenic signaling in MASH and demonstrates that targeting this pathway, either by disrupting palmitoylation-dependent mislocalization or by hepatocyte-specific Nat10 inhibition, ameliorates liver fibrosis with concurrent metabolic benefit.