GPR75, a G protein-coupled receptor implicated in human obesity through loss-of-function variants, has emerged as a promising regulator of energy and metabolic homeostasis. To dissect its tissue-specific functions, we generated a humanized floxed Gpr75 mouse model with conditional deletions in the brain and adipose tissue. Mice with brain-specific Gpr75 deletion using Nestin-Cre were resistant to diet-induced obesity, primarily through suppressed food intake and modest increases in energy expenditure. In contrast, adipocyte-specific deletion of Gpr75 had minimal effects on systemic metabolism but modestly enhanced mitochondrial oxygen consumption in brown adipose tissue under cold exposure. Gpr75 expression was up-regulated in key brain regions and down-regulated in white adipose tissue under high-fat diet conditions, supporting a predominant central role in metabolic adaptation. Histological and transcriptomic analyses further revealed depot-specific effects on adipocyte morphology and hepatic lipid accumulation in global knockouts. These findings position GPR75 as a critical regulator of central energy balance and provide a mechanistic framework for developing brain-targeted therapies against obesity.

The regulatory mechanism of leptin's afferent action in the brain is contingent upon the efferent sympathetic innervation of white and brown adipose tissues. Nonetheless, the peripheral regulation governing the afferent-efferent balance remains ambiguous. Here we show the enriched expression of both leptin receptor (Lepr) and β2-adrenergic receptor (Adrb2) in perineurial cells that form a barrier around sympathetic ganglia and nerve bundles in adipose tissues, using single-cell RNA sequencing on mouse sympathetic ganglia. Lepr+ sympathetic perineurial cells (SPCs) are molecularly similar to endothelial cells. Conditional knockout of Adrb2 in Lepr+ cells, including SPCs, predisposes male mice to obesity by lowering energy expenditure and thermogenesis without affecting food intake. Notably, obesity-associated hyperleptinaemia causes apoptosis in SPCs, disrupting the perineurial barrier and concomitant adipose sympathetic neuropathy. This deleterious effect can be reversed by partial reduction of leptin or sympathomimetic β2-adrenergic receptor agonism. Clinically, we observed a male-specific synergistic effect of LEPR and ADRB2 polymorphisms on increased body mass index risk in a large European population. We propose that SPCs coordinate the afferent and efferent arms of the neuroendocrine loop of leptin action to regulate energy expenditure and body weight.

BACKGROUND AND AIMS:During long-term weight gain, extracellular matrix remodeling in adipose tissue elevates local and systemic endotrophin, potentially contributing to metabolic dysfunction. Whether short-term increases or reductions in fat mass modulate circulating endotrophin concentrations in humans remains unclear. We aimed to determine the relationship between short-term changes in fat mass (kg and fat percentage points) and circulating endotrophin levels, and to explore whether endotrophin mediates the effects of adiposity on lipid profiles. METHODS:Secondary analysis of the pooled individual participant data from two clinical trials. One trial randomized 42 healthy adults (52.4% women, 26-49 years) to one of the following six-month interventions: (a) weight maintenance, (b) 25% caloric restriction, (c) 12.5% caloric restriction and 12.5% increased energy expenditure, or (d) very low-calorie diet. The other trial enrolled 31 healthy adults (19.4% women, 20-40 years) and exposed them to an eight-week 40% overfeeding. Fat mass, circulating endotrophin, and circulating lipid profile were measured before and after these interventions. RESULTS:Considering all participants, the changes in fat mass ranged from -11.0 to +7.0 kg or -9.6 to +5.7 percentage points. Changes in fat mass were positively associated with changes in circulating endotrophin (unstandardized B-coefficient [95% CI] = 0.76 [0.45, 1.07] ng/mL/kg and 0.89 [0.51, 1.28] ng/mL/percentage point, P < 0.001). Exploratory mediation analyses showed that endotrophin mediated 15% [4, 51] of the effect of fat mass on total cholesterol. CONCLUSION:Changes in fat mass, including loss and gain, are associated with corresponding changes in circulating endotrophin, which may partially mediate metabolic effects. Future studies should test whether endotrophin represents a therapeutic target for metabolic health in humans.

Macrophages orchestrate tissue remodeling, inflammation, and metabolic dysfunction in obesity, but the role of macrophage-intrinsic extracellular proteolysis in immunometabolic regulation remains unclear. Matrix metalloproteinase-14 (MMP14), a membrane-bound protease, is strongly induced during monocyte-to-macrophage differentiation and further elevated in adipose tissue macrophages from high-fat diet (HFD)-fed mice. Pharmacological inhibition or myeloid-specific deletion of Mmp14 impaired macrophage differentiation, proliferation, migration, phagocytosis, and inflammatory activation in response to obesity-associated adipose tissue signals. Mechanistically, MMP14 promoted inflammatory programming by increasing endotrophin generation and enhancing TLR4-NFκB signaling. MMP14 also reprogrammed macrophage lipid metabolism by suppressing lipolysis and promoting lipid accumulation, altering metabolic communication with neighboring cells. In vivo, myeloid-specific Mmp14 deletion protected mice from HFD-induced insulin resistance, dyslipidemia, hepatic steatosis, adipose inflammation, and fibrosis. These findings identify macrophage MMP14 as a key mediator linking extracellular matrix remodeling with inflammatory and metabolic dysfunction in obesity.

BACKGROUND Despite antiretroviral therapy (ART), people with HIV (PWH) are at heightened risk for insulin resistance (IR) and type 2 diabetes (T2D). Subcutaneous adipose tissue (SAT) fibrosis contributes to metabolic disease, but its role in IR among PWH is unknown. We investigated the relationship between SAT fibrosis and IR in PWH, along with transcriptional signatures to distinguish it from SAT fibrosis due to obesity.METHODS We analyzed body composition and SAT fibrosis (hydroxyproline) in 46 PWH and 74 people without HIV (PWoH), excluding individuals with T2D. We examined fibrosis-related gene transcription in the SAT using a targeted panel and measured plasma endotrophin, a marker of extracellular matrix (ECM) remodeling.RESULTS PWH had substantially more SAT fibrosis than PWoH, notably in nonobese individuals. Moreover, SAT fibrosis in these PWH was strongly associated with IR, independent of prior legacy ART or ongoing integrase strand inhibitor treatment. This SAT fibrosis was highlighted by a distinct transcriptional pattern marked by upregulation of COL14A1, key immune-related genes (e.g., CCL4, NLRP3), and pathways governing ECM remodeling and immune activation, as well as downregulation of thermogenic, lipid metabolic, and insulin signaling pathways. Plasma endotrophin levels were also elevated in PWH and correlated independently with SAT fibrosis.CONCLUSION SAT fibrosis was associated with IR independent of obesity in PWH and was mirrored by circulating endotrophin levels, offering a plausible noninvasive biomarker for early intervention. The distinct transcriptional signature of HIV-associated SAT fibrosis highlights candidate mechanisms that may underlie metabolic risk and offer therapeutic avenues in this population.TRIAL REGISTRATION ClinicalTrials.gov NCT03022682.FUNDING R01DK141041; R01DK112304; R56DK133997; K08DK124679; T32DK007418; P30DK098722; P30AI027763; Robert Wood Johnson Foundation; Harold Amos Medical Faculty Development Program.

Leptin, secreted by adipocytes, conveys the status of peripheral energy stores to the brain to regulate appetite and metabolism. Although sympathetic activation via β3-adrenergic receptors (β3-ARs) has been shown to suppress leptin expression, it remains unclear whether this regulation arises directly within adipocytes or through other populations. Additionally, it is unclear whether β3-AR signaling contributes to the fasting-induced reduction in leptin. To address this, we generated a novel Adrb3 transcriptional block mouse (Adrb3TB/TB) enabling global β3-AR inactivation and adipocyte-specific re- expression (Adrb3TB/TB; Adipoq-Cre). Global loss of Adrb3 increased plasma leptin levels, while re-expression in adipocytes normalized leptin and restored β3-AR agonist-induced leptin suppression. Analysis of Lep mRNA revealed depot specific regulation, with β3-AR signaling predominantly affecting gonadal and subcutaneous white adipose tissue, while brown adipose tissue responses were modest and variable. Despite these effects, fasting for 48 hours comparably reduced plasma leptin and Lep mRNA in both wild-type (WT) and Adrb3TB/TB mice, indicating that β3-AR signaling is not required for the fasting-induced decline in leptin. Collectively, these findings establish adipocyte β3-AR signaling as a key regulator that constrains leptin synthesis under basal and stimulated conditions in male mice, but not during energy deprivation. Together, these findings clarify the role of adipocyte β3-adrenergic signaling in leptin regulation and provide new insight into the sympathetic control of adipose tissue function.

Activation of glucagon-like peptide-1 receptor (GLP-1R) could affect cancer treatment responses through direct action in tumor or immune cells. However, the field lacks a comprehensive assessment of GLP-1R expression and activity across human tumors. Herein, we report detection GLP-1R across multiple human tumor types and focus on triple-negative breast cancer (TNBC) for deeper analysis. In TNBC, GLP-1R is present in immune and tumor cell compartments. GLP-1 treatment of cancer cells activated survival pathways, drove proliferation, induced paclitaxel resistance and dampened cytokine secretion, effects that required expression of GLP-1R. Spatial transcriptomics of human tumors revealed that GLP-1 exposure remodeled the tumor microenvironment, promoted a mesenchymal transition in malignant cells and disrupted productive macrophage inflammation in tumor-proximate niches. Patients taking GLP-1 drugs during neoadjuvant chemotherapy experienced reduced pathological complete response rates (pCR: 30.8%) compared to controls (65%, p<0.001). Thus, GLP-1-exposure acts on tumor and immune cells to impair chemoimmunotherapy efficacy in TNBC.

Background/Objectives: Signaling mediators of PPARγ influence pathways involved in adipogenesis, lipid storage, inflammation, energy-related processes, and glucose utilization. Recent research indicates that PPARγ coregulators, recruited or released during ligand binding, govern specific gene pathways. It was recently discovered that Gαq, a heterotrimeric G protein subunit, also signals to PPARγ and may significantly affect adipogenesis and glucose sensitivity. Methods: To explore Gαq’s role in adipocytes, we generated CRISPR-mediated Gαq (Gnaq) knockout (Gnaq KO) and scramble control cells from 3T3-L1 preadipocytes. Results: The absence of Gαq resulted in increased lipid accumulation and elevated serine 273 (but not serine 112) phosphorylation of PPARγ. Gαq deficiency also decreased mitochondrial abundance and respiration in response to PPARγ ligands such as rosiglitazone, pioglitazone, and troglitazone. RNA sequencing comparing differentiated Gnaq KO and control adipocytes identified over 800 differentially expressed genes, including those associated with enhanced lipid metabolism and reduced inflammation. Corresponding PamGene kinome profiling showed increased serine/threonine kinase activity and decreased phosphotyrosine kinase signaling in Gnaq KO adipocytes. Conclusions: These findings support Gαq as a regulator of adipocyte function, linking kinase signaling pathways to PPARγ-mediated transcription. This research provides mechanistic insights into targeting Gαq as a potential treatment for individuals with obesity and metabolic disorders.

Lipedema is a chronic adipose tissue condition that primarily affects women. Despite increasing recognition of lipedema, the condition remains poorly understood and lacks standardized diagnostic criteria or confirmatory tests. Variability in definitions and measurement across clinical and research settings impedes comparability across studies, constraining the evidence base needed to support future advances in clinical practice and patient care. To address challenges associated with inconsistent definitions and data collection, the Lipedema Foundation (LF) partnered with clinicians, researchers, and biostatisticians to develop a Lipedema Common Case Report Form (CCRF). The CCRF was designed to be a research data harmonization tool and is not intended to define diagnostic standards or guide clinical treatment decisions. Its development involved review of published lipedema clinical guidelines and collaborative work to define data elements and attributes for inclusion. When they existed, validated or standardized measures were incorporated directly. When no suitable standardized measures were available, an iterative and collaborative process was used to develop lipedema-specific Common Data Elements (CDEs). The initial version of the CCRF was piloted in participants with and without lipedema, and updates based on participant and clinician feedback were incorporated into the CCRF. A biostatistical review evaluated data completeness, quality, and structure, leading to additional refinements. The final Version 1 instrument consists of 682 CDEs organized into four classifications: (1) Core, (2) Supplemental Highly Recommended, (3) Supplemental, and (4) Exploratory. The current version is prepared for dissemination in the field. By disseminating the CCRF broadly and encouraging adoption in all lipedema research beginning in 2026, including all newly initiated LF-funded projects, LF intends to evaluate its use with grantees and iterate systematically to achieve consistent and comparable data collection. The CCRF provides a structured framework for harmonized data collection that may facilitate comparability across studies and support future development of standardized diagnostic and research methodologies.

One of the most striking features of the adipose depot surrounding the prostate [periprostatic adipose tissue (PPAT)] is that its accumulation is independent of body mass index. Its volume varies considerably between individuals, with some patients exhibiting abundant PPATs, which have been correlated to the occurrence of aggressive prostate cancer (PCa). However, abundant PPAT is not well defined at the biological level. We used a new statistical approach to define abundant PPAT by normalizing PPAT volume to prostate volume in a cohort of 351 patients using a linear regression model. Applying this definition, we confirmed the link between abundant PPAT and PCa aggressiveness, thereby validating our approach. At the biological level, we showed that abundant PPAT exhibited extensive extracellular matrix remodeling, notably of the collagen network, decreasing the mechanical constraints in hypertrophic adipocytes, leading to inflammation-free expansion. Degradation of the most abundant collagen in adipose tissue (AT), collagen VI, was associated with increased production of endotrophin, a signaling peptide derived from AT that was also elevated in the urine of patients with abundant PPAT confirming the clinical relevance of our results. These results highlight a unique mechanism of expansion of an adipose depot and open new mechanistic avenues to explain its role in prostate-related disorders. © 2026 The Pathological Society of Great Britain and Ireland.

Extracellular vesicles (EVs) are nano-sized, membrane-delimited, particles released by cells that carry signaling macromolecules. A major pathway of EV production is potentiated by neutral sphingomyelinase 2 (SMPD3/nSMAse2), an enzyme that generates ceramide from sphingomyelin. In our attempt to study this pathway in adipocytes of male mice, we discover that the elimination of SMPD3 from adipocytes in vivo triggers a signal to surrounding immune cell-like preadipocytes to release EVs that carry SMPD3 mRNA. This results in a widespread increase in SMPD3 mRNA in purified null adipocytes without a change in the transcripts of other enzymes involved in ceramide metabolism. These results point to a selective mechanism by which specific mRNA molecules are acquired from the microenvironment to a level that can restore expression of mRNA and protein in a cell that is depleted of the corresponding genetic information.

Iron overload has emerged as a significant risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD), a growing global health concern. Despite this association, the precise mechanisms by which hepatic iron and its regulatory genes connect liver pathology to systemic metabolic dysfunction remain elusive. Here, we demonstrate that humoral signals originating from iron-overloaded hepatocytes acted as critical mediators driving systemic metabolic dysfunction in MASLD. Ferroportin (FPN, SLC40A1), the sole cellular iron exporter, exhibited markedly reduced expression in hepatocytes of both patients with MASLD and mouse models of the disease, concomitant with hepatic iron accumulation. Functionally, hepatocyte-specific FPN deletion significantly exacerbated diet-induced obesity and insulin resistance, with these metabolic perturbations accompanied by decreased energy expenditure and impaired thermogenic capacity. Mechanistically, we establish that hepatic iron accumulation resulting from FPN deficiency enhanced the production of 2 specific hepatokines, fetuin-A and LECT2, through activation of the transcription factor FoxO1. Notably, therapeutic interventions - including genetic silencing of these hepatokines, hepatocyte-specific FPN overexpression, or oral iron chelation - effectively reversed the metabolic dysfunction phenotypes. These findings provide critical insights into the pathophysiological mechanisms linking MASLD to systemic metabolic disorders and highlight promising therapeutic strategies to combat these diseases.

Cardiomyocyte growth is tightly controlled by multiple signaling pathways. Identification of master kinases in this process is essential in exploring potential targets for the treatment of pathological cardiac hypertrophy and heart failure. Here we identified the mTORindependent activation of ribosomal protein S6 kinase b1 (Rps6kb1) during cardiomyocyte growth. By utilizing phosphoproteomics in primary neonatal rat ventricular myocytes, we revealed Rps6kb1 as one of most activated kinases under growth stimulation. We further demonstrated the role of Rps6kb1 phosphorylation in pathological cardiac hypertrophy and heart failure. We showed that the phosphorylation of multiple sites in Rps6kb1, including T367 in the kinase domain and S418/T421/S424 in the C-terminal domain, is not directly regulated by the activity of mTOR but coupled with the activation of the MEK1/ERK axis. In mice, cardiomyocyte-specific deletion of Rps6kb1 significantly inhibited both constitutively active ERK-and pressure overload-induced cardiac hypertrophy. In contrast, cardiomyocytespecific overexpression of wild-type Rps6kb1, rather than the phosphorylation-defective mutant, elevated cardiac hypertrophy and augmented pressure overload-induced heart failure. In conclusion, our findings reveal that the MEK/ERK axis primes Rps6kb1 activation through phosphorylation of 2 separate domains of Rps6kb1, which may play an essential role in cardiac hypertrophy and heart failure under hemodynamic stress.

ContextLong COVID is characterized by persistent symptoms ≥ 3 months after acute SARS-CoV-2 infection. To date, the underlying pathophysiology is unclear.ObjectiveTo characterize the immune and metabolic features of Long COVID and the potential role of viral persistence in adipose tissue.DesignCase-control, cross-sectional study under the RECOVER initiative.SettingMaine, Louisiana, and Kentucky.ParticipantsAdults from the RECOVER study with high or low symptom burden assessed by the PROMIS scoring system or the Long COVID RECOVER Index (LCRI), matched by age, sex, BMI comparing post infected individuals with Long COVID vs those without sequelae.Main outcome measuresThe primary outcome was a difference in T cell mitochondrial respiration by symptom severity. Secondary outcomes included glucose tolerance, body composition, T cell surface markers, subcutaneous adipose biopsy.ResultsThere were 54 participants, 80% female, mean age was 51.7 years, mean BMI 31. Time from initial infection was 894 days. The participant cohort by symptom burden was elucidated using a PROMIS symptom score subdivided by the following: High Symptom Burden (HSB) >15:n=25, Intermediate Symptom Burden (ISB) 10-15: n=14 and Low Symptom Burden (LSB) <10;n=15. Using the LCRI, n=15 were Long COVID+ (LC+) and n=39 were Indeterminate. The primary outcome, T-cell oxidative phosphorylation, did not differ between LC+ and Indeterminate nor by PROMIS scores. BMI and fat mass did not differ but T cell glycolytic activity was greater in those with LC+ vs Indeterminate. Lean mass and femoral BMD trended lower in the HSB vs LSB by both classifications. Prevalence of Type 2 diabetes did not differ by symptom scores, but HOMA-IR was higher and HOMA-B was lower in LC+ vs Indeterminate. SARS-CoV-2 viral RNA was not detectable in subcutaneous adipose tissue biopsies. CD26+ T cell number, and DPP-4 (CD26) activity were higher in the HSB and correlated significantly with symptom scores (r=0.52, p<0.01); plasma cytokines and stimulated T-cell cytokines did not differ by symptom group in either classification.ConclusionsIndividuals with Long COVID symptoms show subtle impairments in glucose tolerance, serum leptin, lean mass and enhanced T-cell DPP-4 activity. Participants with Long COVID have subtle changes in glucose metabolism that are not driven by SARS-CoV-2 virus in subcutaneous adipose tissue.

Caloric restriction (CR) extends lifespan, yet the convergent immunometabolic mechanism of healthspan remains unclear. Using longitudinal plasma proteomics analyses in humans achieving 14% CR for 2 years, we identified that inhibition of the complement pathway is linked to lower inflammaging. The protein C3a (and its cleaved form) was significantly lowered by CR, thus reducing inflammation emanating from three canonical complement pathways. Interestingly, circulating C3a levels are increased during aging in mice, with visceral adipose tissue macrophages as the predominant source. In macrophages, C3a signaling via ERK elevated inflammatory cytokine production, suggesting the existence of an autocrine loop that promotes inflammaging. Notably, long-lived FGF21-overexpressing mice and PLA2G7-deficient mice exhibited lower C3a in aging. Specific small molecule-mediated systemic C3 inhibition reduced inflammaging, improved metabolic homeostasis, and enhanced healthspan of aged mice. Collectively, our findings reveal that complement C3 deactivation is a metabolically regulated inflammaging checkpoint that can be harnessed to extend healthspan.

Following the trends of the adult obesity epidemic, and worsened by school disruptions during the coronavirus disease 2019 pandemic, childhood obesity prevalence has reached unprecedented levels. The health implications for this generation are especially concerning, as childhood-onset obesity has more severe health consequences than weight gain that begins in adulthood, including increased risk of type 2 diabetes and diabetes-related complications. The complexity of obesity treatment has been challenging, including remarkable heterogeneity in obesity phenotypes and treatment responses among both adults and children. Many in the field have therefore highlighted a need for precision medicine approaches in obesity treatment across age-groups. This includes a need for precision risk stratification to better target treatment intensity, which will require a better understanding of the earliest stages of metabolic syndrome pathophysiology. The health, function, and distribution of adipose tissue have been established as important determinants of metabolic health in both childhood- and adult-onset obesity, making adipose tissue a promising target for understanding phenotypic heterogeneity in obesity. Here, we provide a brief overview of the current limited understanding of adipose tissue biology during childhood development and discuss opportunities for further research into adipose-centric precision medicine approaches in childhood-onset obesity and type 2 diabetes. ARTICLE HIGHLIGHTS:Treatment options for childhood obesity are expanding, but precision medicine approaches, including strategies for precision risk assessment, are needed to appropriately target treatment intensity. Parameters of adipose tissue dysfunction are better predictors of metabolic syndrome than body size, and therefore adipose tissue represents a prime candidate for research approaches in understanding the pathophysiology of insulin resistance and in identifying biomarkers of future prognosis. Expanded developmental research on pediatric adipose tissue in both mice and humans is needed to understand the pathophysiology of childhood-onset obesity and to develop precision treatment approaches.