A resurgence in glucagon research has repositioned this pancreatic hormone as a promising target in the treatment of obesity and related metabolic disorders. Glucagon is classically known for contributing to glucose homeostasis, but emerging evidence points to a much wider role in metabolism, including energy balance and liver health. These findings are fueling attempts to understand how to leverage glucagon signaling to treat obesity and metabolic dysfunction-associated steatohepatitis (MASH). Due to potential hyperglycemic effects of glucagon signaling, most investigational compounds are dual agonists of both the glucagon and glucagon-like peptide-1 (GLP-1) receptors to harness the antihyperglycemic and anorectic effects of the latter hormone, analogs of which such as semaglutide are already proven to be potent obesity medications. Glucagon receptor/GLP-1 receptor dual agonists reduce food intake, decrease hepatic fat, and increase energy expenditure in animal models of obesity and MASH. In early clinical trials, some dual agonists substantially reduced body weight, hepatic steatosis, and hepatic fibrosis. Whether they are more effective than GLP-1 receptor mono-agonists remains to be established in definitive head-to-head studies. The precise balance between glucagon and GLP-1 signaling within individual compounds appears important for overall therapeutic effects-including glycemic control, which worsened with some dual agonists. However, the two most clinically advanced compounds-mazdutide (approved for chronic weight management and type 2 diabetes in China) and survodutide (ongoing global phase 3 trials)-had potent weight-loss and antihyperglycemic effects in people with obesity, with survodutide also improving liver health in people with MASH. Therefore, the research into glucagon physiology that led to glucagon receptor/GLP-1 receptor dual agonists is translating to advantageous new therapies for the highly prevalent diseases of obesity and MASH.

Obesity is a chronic, recurrent, and progressive disease caused by energy imbalance. N6-methyladenosine (m6A) modification regulates fat thermogenesis, potentially counteracting obesity. Mogroside V (MV) is a triterpene glycoside extracted from Siraitia grosvenorii and has shown beneficial effects in models of obesity. However, its underlying mechanism remains unknown. The objective of this study is to investigate the effects of MV on adipose thermogenesis and explore the mechanism of m6A modifications in mediating these effects. Mitochondrial respiration analysis, histological and molecular biological methods were used to investigate the thermogenesis in differentiated C3H10T1/2 brown adipocytes and adipose tissue in high-fat diet (HFD)-fed mouse models, respectively. Stable cell models with overexpression or knockdown of fat mass and obesity-associated protein (FTO) were generated to investigate the effects of FTO on m6A modification and thermogenesis in brown adipocytes. Methylated RNA immunoprecipitation-quantitative-PCR (MeRIP-qPCR) and RIP-qPCR analysis were used to reveal the potential downstream molecular targets of FTO. MV improved HFD-induced obesity and metabolic dysfunction in mice. MV also increased uncoupling protein 1 (UCP1) expression in brown adipose tissue and enhanced mitochondrial respiration and expression of peroxisome proliferator activated receptor γ coactivator 1α (PGC1α) and UCP1 in differentiated C3H10T1/2 cells. Further analysis of the relevant molecular mechanisms showed that MV suppressed FTO expression, thereby increasing m6A modification of LETM1 domain-containing protein 1 (Letmd1) mRNA. The m6A-modified Letmd1 transcript was recognized by the m6A reader YTH domain-containing protein 2 (YTHDC2), thereby increasing the stability of Letmd1 mRNA. The increased Letmd1 mRNA levels were correlated with increased LETMD1 protein abundance, which subsequently enhanced the expression of PGC1α and UCP1, ultimately promoting brown adipocyte thermogenesis. MV promoted brown adipocyte thermogenesis through the FTO-m6A-LETMD1-UCP1 axis, suggesting a potential therapeutic strategy for obesity.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), initially developed for the treatment of type 2 diabetes and obesity, are increasingly recognised as multi-system agents with cardiovascular, renal and anti-inflammatory benefits. Emerging evidence suggests that their pleiotropic metabolic and immunomodulatory effects may have therapeutic relevance in chronic lung diseases. The lung is a metabolically active organ in which obesity, insulin resistance and systemic inflammation contribute to disease susceptibility, progression and treatment response. Chronic lung diseases such as asthma, COPD, pulmonary hypertension and interstitial lung disease share overlapping inflammatory, vascular and fibrotic pathways that may be modifiable through GLP-1 RA-based therapies. Preclinical studies demonstrate that GLP-1R signalling influences airway inflammation, oxidative stress, endothelial function and fibroblast activation. Observational and early clinical data suggest potential benefits in asthma control, exacerbation reduction in COPD, vascular remodelling in pulmonary hypertension and a reduction in all-cause mortality in interstitial lung disease. In addition to weight loss and glycaemic improvement, GLP-1 RAs exert direct anti-inflammatory and immune-regulatory effects that may act independently of metabolic change. Despite promising mechanistic and translational signals, high-quality randomised controlled trials with GLP-1 RAs in pulmonary populations remain limited. Key questions include patient selection, interaction with established anti-inflammatory and antifibrotic therapies, and the relative contribution of metabolic versus direct pulmonary effects. This review aims to synthesise current mechanistic, experimental and clinical evidence supporting GLP-1 RA use in chronic lung disease and outlines future research priorities within a precision-medicine framework.

Obesity-associated adipose inflammation and gut dysfunction represent critical targets for dietary intervention. Tart cherry juice (TCJ)-derived anthocyanins (ACNs) exhibit potent anti-inflammatory and gut-protective bioactivity, but their poor stability and low oral bioavailability limit efficacy. Although nanotechnology can improve ACN delivery, conventional nanocarriers contain surfactants or emulsifiers that may impair gut health with chronic use. To overcome these challenges, we developed a surfactant-free nanoparticle platform using polysaccharides. Void nanoparticles (Vnano) were fabricated by ionic gelation of chitosan and carboxymethyl chitosan, followed by ACN adsorption through hydrogen bonding and electrostatic interactions to generate ACN-loaded nanoparticles (Tnano). Optimized Tnano achieved 80% ACN adsorption efficiency with spherical morphology (about 200 nm), narrow size distribution, and positive zeta potential (23 mV). Compared to free TCJ, Tnano demonstrated sustained ACN release, and fluorescence imaging showed dose- and temperature-dependent binding of the chitosan nanoparticles to 3T3-L1 preadipocytes. Tnano more effectively suppressed lipopolysaccharide (LPS)-induced inflammation, reducing interleukin-6 and monocyte chemoattractant protein-1 secretion by 39% (p < 0.0001) and 35% (p = 0.0316) in preadipocytes, and by 56.8% (p = 0.05) and 20% (p < 0.0001) in mature adipocytes, respectively, compared to LPS groups. Compared to control, Tnano reduced adipogenic lipid accumulation by 35%, versus only 14.2% for TCJ (p = 0.0003). As a proof of concept for future oral delivery applications, Tnano was encapsulated within an alginate hydrogel shell by electrospray to form a nano-in-micro format. This fully natural polysaccharide-based nanoplatform offers a strategy to enhance anthocyanin bioavailability and combat obesity-associated inflammation and metabolic disease.

Sustained upregulation of hepatic gluconeogenesis is a major source of hyperglycemia in type 2 diabetes, and obesity is the primary driver. However, a substantial subset of obese individuals does not progress to diabetes, a condition termed metabolically healthy obesity, and the underlying mechanism has long remained unclear. ROS act both as physiological signals and as pathological drivers, but no molecular marker characterizes the transition between these two states, making it difficult to time antioxidant intervention against oxidative modification-mediated damage. Here we show that the activity of phosphoenolpyruvate carboxykinase 1 (PCK1), a key enzyme of gluconeogenesis, is redox-sensitive. Excess accumulated ROS induce reversible sulfenylation at cysteine 288, near the catalytic center, directly driving gluconeogenesis in the absence of insulin. We therefore propose a dual regulatory model of glucose metabolism signaled by hepatic oxidative load. At low oxidative load, ROS activate AMP-activated protein kinase (AMPK) via glutathionylation to promote glycolysis, whereas once the load accumulates, PCK1 is activated via sulfenylation to drive gluconeogenesis, accompanied by a decline in AMPK glutathionylation. Hepatic oxidative load therefore acts as a switch governing the direction of hepatic glucose flux. In diabetic mice, the two modifications show a complementary, stage-dependent distribution paralleling this accumulation, with AMPK glutathionylation predominating in the compensatory stage and PCK1 sulfenylation becoming dominant as the load accumulates further. Their reciprocal dynamic therefore serves as an early warning signal for the transition of ROS from physiological to pathological states. On this basis, we intervened as oxidative load began to accumulate, and found that lowering hepatic ROS prevented the oxidative activation of PCK1, suppressed gluconeogenesis and ameliorated hyperglycemia. These findings reveal that the key gluconeogenic enzyme is directly regulated by redox signals independently of insulin, providing a molecular basis for the heterogeneity of diabetes progression in obesity and for the precise timing of antioxidant intervention.

Large volumes of whey generated during dairy processing are underutilized or discarded, creating environmental burdens. Recovering bioactive compounds from camel whey offers a sustainable valorization startegy. This study developed a one-step purification method for camel lactoferrin, generated trypsin-derived hydrolysates, and evaluated their metabolic and antioxidant effects in cafeteria diet-induced obese rats. Lactoferrin was purified using DEAE-Sepharose anion-exchange chromatography, yielding a protein concentration of 12.13 ± 1.25 mg/mL (n = 5), 87.3% recovery , and ~90% purity. Obese Wistar rats received   whole camel whey, purified lactoferrin, or its hydrolysate (100 mg/kg/day, 2 weeks). Body weight, glycemic control, lipid profiles, hepatic/renal biomarkers, and tissue oxidative stress were assessed. Obesity was associated with increased body weight, serum glucose, insulin, lipids, hepatic and renal biomarkers, with severe oxidative stress in the liver, adipose tissue and muscle. All treatments significantly improved these alterations (p < 0.05), with lactoferrin hydrolysates showing the strongest protective effects (p < 0.001), reducing weight gain, improving lipid and glucose homeostasis, and restoring antioxidant defenses. These findings highlight camel whey as a valuable source of bioactive ingredients and demonstate the potential of simplified lactoferrin recovery to support circular bioeconomy strategies and the development of nutritional approches targeting obesity-related metabolic disorders.

Background Maternal obesity is an increasingly important public health concern and has been consistently associated with adverse pregnancy outcomes, including hypertensive disorders of pregnancy, cesarean delivery, fetal overgrowth, and preterm birth (PTB). Local institutional data remain valuable because patient characteristics and obstetric practice patterns may vary across healthcare settings. This study aimed to evaluate the unadjusted and adjusted associations between pre-pregnancy obesity and selected adverse obstetric outcomes - hypertensive disorders of pregnancy, postpartum hemorrhage (PPH), cesarean delivery, macrosomia, and PTB - among women delivering at Zhordania Medical Center, a secondary care center in Tbilisi, Georgia. Methods This retrospective cohort study included 428 pregnant women with documented pre-pregnancy body mass index (BMI) who delivered at Zhordania Medical Center during the study period. Participants were divided into two groups according to pre-pregnancy BMI: BMI ≥ 30 kg/m[2] (obese group, n = 145) and BMI < 30 kg/m[2] (non-obese group, n = 283). The outcomes of interest were hypertensive disorders of pregnancy, PPH, cesarean delivery, macrosomia, and PTB. Categorical variables were summarized as frequencies and percentages, and group comparisons were performed using the chi-squared test or Fisher's exact test, as appropriate. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using univariable logistic regression; multivariable logistic regression, adjusting for maternal age, parity, and (where estimable) prior cesarean delivery, was subsequently performed using patient-level data. A two-sided p-value < 0.05 was considered statistically significant. Results Women with pre-pregnancy BMI ≥ 30 kg/m[2] had significantly higher odds of hypertensive disorders of pregnancy than women with BMI < 30 kg/m[2] (26/145 vs. 14/283; OR 4.20, 95% CI 2.12-8.32; p < 0.001; adjusted OR 3.80, 95% CI 1.88-7.69). Cesarean delivery was also more common in the obese group (85/145 vs. 126/283; OR 1.77, 95% CI 1.18-2.65; p = 0.006; adjusted OR 1.83, 95% CI 1.19-2.81). Macrosomia, defined as birth weight > 4,000 g, occurred more frequently among women with obesity (23/145 vs. 23/283; OR 2.13, 95% CI 1.15-3.95; p = 0.014; adjusted OR 2.02, 95% CI 1.07-3.82). No statistically significant associations were observed for PPH (9/145 vs. 11/283; OR 1.64, 95% CI 0.66-4.04; p = 0.28) or PTB (15/145 vs. 19/283; OR 1.60, 95% CI 0.79-3.26; p = 0.19), though the achieved sample provided limited power (approximately 21% and 27%, respectively) to detect effects of this magnitude. Conclusions Pre-pregnancy obesity was associated with increased odds of hypertensive disorders of pregnancy, cesarean delivery, and macrosomia in this retrospective cohort from a secondary care center in Georgia, independent of maternal age, parity, and prior cesarean delivery where adjustment was feasible. These associative findings highlight the importance of preconception counseling and enhanced antenatal surveillance for women with obesity, although causal inference requires confirmation in larger, prospective studies.

Thioredoxin-interacting protein (TXNIP) is a multifunctional regulatory protein of the α-arrestin family that acts as a redox sensor, an energy-responsive molecule, and a transcription-associated regulator. TXNIP has emerged as a key regulator of skeletal muscle homeostasis and has been implicated in the pathogenesis of multiple muscle disorders. Skeletal muscle is a principal site of systemic glucose disposal, accounting for more than 70% of insulin-stimulated glucose uptake in the human body. TXNIP has been implicated in sarcopenia, obesity-related insulin resistance, limb ischemia-induced muscle injury, disuse muscle atrophy, and hereditary muscular dystrophy through multiple mechanisms, including glutathione metabolic regulation, ferroptosis, NLRP3 inflammasome activation, impaired GLUT4 membrane translocation, and altered mitochondrial substrate oxidation. Recent advances in gene editing, single-cell sequencing, metabolomics, and human clinical research have enabled a more detailed characterization of TXNIP-related molecular mechanisms in skeletal muscle. This review provides a systematic synthesis of recent evidence on TXNIP in skeletal muscle, organized around seven themes: its molecular characteristics, expression and regulatory patterns in skeletal muscle, physiological functions, disease-specific pathogenic mechanisms, intervention-related regulatory networks, current limitations, and future perspectives. This review aims to provide a mechanistic rationale for targeting TXNIP as a potential strategy for the prevention and treatment of skeletal muscle-related diseases.