Although the pathogenesis of genetic obesity is becoming increasingly clear, effective treatments remain lacking, particularly for obesity caused by melanocortin 4 receptor (MC4R) deficiency. The activity of MC4R is strictly regulated by its endogenous ligands: α-melanocyte-stimulating hormone (α-MSH) binds to MC4R and transmits anorexigenic and energy-expenditure signals, whereas agouti-related protein (AgRP) exerts an antagonistic effect by binding to the receptor, competitively inhibiting α-MSH action and promoting appetite. Current options, such as lifestyle modifications and bariatric surgery, have limited efficacy, highlighting the need for accessible pharmacological interventions. This review evaluates glucagon-like peptide-1 (GLP-1) receptor agonists in MC4R-deficient obesity. We conducted a comprehensive literature search across databases, including PubMed and Web of Science, compiling data from clinical trials, case reports, and basic research studies published up to 2025, with a focus on the efficacy, safety, and mechanism of action of drugs such as liraglutide, semaglutide, and tirzepatide in patients with MC4R deficiency. Evidence indicates these agents induce significant weight loss, appetite suppression, and metabolic improvements via mechanisms independent of intact MC4R signaling. Their weight-loss effects are comparable to those seen in common obesity, with additional benefits for comorbidities like insulin resistance and dyslipidemia. These findings support the GLP-1 pathway as an alternative to impaired MC4R, offering a viable treatment. Understanding their efficacy and mechanisms provides new treatment options for this rare condition and offers evidence for genetically specific personalized weight management.
Aim: Metabolic dysfunction-associated steatotic liver disease (MASLD) and liver fibrosis are increasingly prevalent among people living with HIV (PLHIV), particularly as metabolic comorbidities such as prediabetes rise. Yet, liver fibrosis risk in PLHIV with prediabetes remains poorly characterised, particularly in sub-Saharan Africa. Non-invasive tests (NITs), including the Fibrosis-4 (FIB-4) Index, are recommended for first-line fibrosis risk stratification. Most lack validation in sub-Saharan African PLHIV. We aimed to estimate liver fibrosis risk and ten-year cirrhosis risk using blood-based NITs in a Tanzanian cohort of PLHIV with prediabetes.
Methods: We conducted a cross-sectional analysis of baseline data from 1,691 PLHIV with prediabetes enrolled in the Metformin Trial (META) Trial in Tanzania. Fibrosis risk was assessed using FIB-4, Metabolic Dysfunction-Associated Fibrosis 5 (MAF-5), NAFLD Fibrosis Score (NFS), and LiverRisk with validated age-adjusted cut-offs. Ten-year cirrhosis risk was estimated using the Cirrhosis Outcome Risk Estimator (CORE).
Results: Participants had a mean age of 49.4 years (SD 9.4); 75.0% were female and 99.2% were Black. FIB-4 classified 65.0% as low risk and 3.04% as high risk. MAF-5 identified 50.26% as high risk, while NFS classified 7.46% as high risk. Less than 1% were medium- to high-risk by LiverRisk. Using CORE, 5.8% had > 1% predicted 10-year cirrhosis risk. Substantial discrepancies were observed.
Conclusion: Multiple NITs identified measurable fibrosis or cirrhosis risk, yet risk classification varied markedly. These findings highlight both the potential utility and major limitations of existing NITs in African HIV and prediabetes settings and underscore the urgent need for locally validated, context-appropriate fibrosis screening tools.
Aim: To develop and internally evaluate machine learning (ML) models for predicting incident cardiovascular-kidney-metabolic (CKM) multimorbidity in Chinese adults with overweight or obesity, and to identify key predictors.
Methods: We included 4,244 participants from the China Health and Retirement Longitudinal Study (CHARLS) with overweight/obesity [body mass index (BMI) ≥
Results: During 3-year follow-up, 648 (15.3%) participants developed incident CKM multimorbidity. Nine predictors were selected: age, depression, pain, health expectation, weight change, dyslipidemia, hypertension, heart disease, and kidney disease. Artificial neural network (ANN) and logistic regression showed the best discrimination (AUC: 0.758 and 0.757) and acceptable calibration in internal testing (Brier score: 0.113 and 0.114). SHAP analysis identified hypertension, dyslipidemia, and depression as top contributors. A nomogram was developed for preliminary risk stratification, but external validation is required before any clinical application.
Conclusion: In this internal evaluation, ANN and logistic regression showed moderate discrimination and acceptable calibration for predicting CKM multimorbidity in Chinese adults with overweight/obesity. Logistic regression performed comparably to complex algorithms yet is simpler; however, external validation is still required before use.
Metabolic dysfunction-associated steatotic liver disease (MASLD) has become one of the most common chronic liver diseases worldwide. With the introduction of the new nomenclature, the management of MASLD is evolving from a conventional liver-centered approach focused primarily on hepatic steatosis, metabolic dysfunction-associated steatohepatitis (MASH), liver fibrosis, and cirrhosis risk toward a broader framework that also addresses heterogeneity in metabolic risk, physical function, tolerance to lifestyle interventions, and long-term prognosis. In recent years, impaired skeletal muscle function, sarcopenia, myosteatosis, vitamin D deficiency, and abnormalities in bone metabolism have increasingly been recognized as clinically relevant conditions associated with MASLD severity, progression risk, and adverse extrahepatic outcomes. Although the underlying biological mechanisms remain incompletely understood, these conditions may serve as clinically meaningful risk markers and potential modifiers of disease progression. This review systematically summarizes the epidemiological associations, proposed shared pathogenic mechanisms, clinical recognition pathways, and integrated intervention strategies linking MASLD, sarcopenia, vitamin D deficiency, and bone metabolic abnormalities. We propose that MASLD complicated by sarcopenia and bone vulnerability may represent a clinically relevant liver-muscle-bone metabolic phenotype. Future management of MASLD should therefore place greater emphasis on preserving muscle function, maintaining bone health, and improving patient-centered outcomes.
Aim: Obesity may induce renal microvascular injury, particularly in peritubular capillaries (PTCs). Early detection of these changes may help patient management. We tested the hypothesis that levels of PTC-derived urinary extracellular vesicles (uEVs) reflecting early renal microvascular alterations would be elevated in obese individuals with preserved kidney function.
Methods: Urinary samples were collected from 22 obese and 11 lean subjects. uEVs were characterized using flow cytometry for markers of PTC (cluster of differentiation 31 [CD31], plasmalemma vesicle-associated protein [PLVAP], and cluster of differentiation 144 [CD144]), angiogenesis (delta-like-ligand-4 [DLL4]), and inflammation (monocyte chemoattractant protein-1 [MCP-1]). For confirmation, PTC density was quantified and correlated with clinical parameters in kidney biopsies from additional matched groups.
Results: Obese individuals had higher body mass index (BMI), glucose, insulin, urinary protein, and urinary MCP-1 levels than lean controls (P < 0.05), indicating metabolic and inflammatory changes, despite no significant difference in serum creatinine or estimated glomerular filtration rate (eGFR). They also exhibited elevated levels of CD31-/PLVAP+/CD144- PTC-derived uEVs expressing DLL4+ and/or MCP-1+ (P < 0.05 each). Levels of angiogenic PTC-derived DLL4+ uEVs correlated with BMI and systemic insulin, vascular endothelial growth factor-A, and angiopoietin-2 levels in our cohorts, whereas MCP-1+ uEVs derived from inflamed PTC correlated with BMI, glucose, blood pressure, and urinary neutrophil gelatinase-associated lipocalin. PTC density was also increased in kidney biopsies from obese individuals, correlating with BMI and glucose.
Conclusion: DLL4+/MCP-1+ PTC-derived uEVs levels reflecting early renal microvascular changes are elevated in obese individuals, despite preserved kidney function. These findings may indicate that microvascular remodeling is dissociated from renal dysfunction in patients with obesity.
Type 2 diabetes (T2D) results from progressive failure of multiple interconnected metabolic nodes. This review synthesizes evidence that β-cell dedifferentiation, mediated by loss of PDX-1, MAFA, and NKX6.1 and by epigenetic silencing of their promoters, may represent a leading mechanism of β-cell dysfunction, potentially preceding apoptotic death. Reduced hepatic insulin clearance through CEACAM1-dependent clearance pathways may contribute to a feedback loop amplifying systemic hyperinsulinemia and worsening peripheral insulin resistance. Adipose tissue dysfunction has been proposed to initiate cascading hepatic and muscular resistance in a subset of T2D phenotypes. Emerging mechanisms include gut microbiota-derived metabolites regulating incretin secretion; cellular senescence and mitochondrial dysfunction as drivers of metabolic aging; and altered bile acid metabolism affecting gluconeogenic regulation. Subcutaneous insulin, reversing the physiological portal-to-peripheral gradient, generates hepatic hypoinsulinemia and peripheral hyperinsulinemia despite adequate total doses. These advances will potentially identify stage-matched therapeutic windows: early insulin resistance for lifestyle intervention and/or SGLT2 inhibitors (SGLT2i); compensatory phase for GLP-1Ra; advanced dedifferentiation for cell replacement. Precision medicine subtyping and multi-node targeting promise improved glycemic control and disease modification.