Search Results (1,595)

The prevention and treatment of cardiovascular disease (CVD) are undergoing a paradigm shift from a lipid-centric approach to a holistic metabolic perspective. Central to this evolution is the gut–fat–heart axis, a sophisticated three-dimensional communication network that integrates neural, endocrine, and immunometabolic signaling to regulate systemic lipid homeostasis. This manuscript systematically explores how the gut microbiota acts as a “metabolic organ” to remotely control host health through the production of bioactive metabolites and the modulation of molecular communication networks. At the physiological level, microbial products such as short-chain fatty acids (SCFAs) and modified bile acids regulate energy balance and lipid synthesis via the FXR-FGF15/19 axis and G protein-coupled receptors. Furthermore, gut hormones like GLP-1 and neuro-reflex pathways involving the vagus nerve provide rapid control over postprandial lipid clearance and feeding behavior. Conversely, pathological dysbiosis triggers the accumulation of harmful metabolites, such as trimethylamine N-oxide (TMAO) and lipopolysaccharides (LPS), which drive lipotoxicity, vascular inflammation, and “dysfunctional HDL” formation. These processes accelerate the progression of atherosclerosis, heart failure, and metabolic syndrome. Finally, the article outlines promising clinical translation strategies, including the development of TMA lyase inhibitors, next-generation probiotics, and the use of phytochemicals to reshape the microbial landscape. By decoding the molecular dialogues within the gut–fat–heart axis, this research provides a novel strategic vantage point for the integrated management of cardiovascular–kidney–metabolic (CKM) syndrome. Full article

Background/Objectives: Obesity-related insulin resistance is accompanied by chronic low-grade inflammation, but the extent to which weight loss modifies circulating cytokines in a sex-specific manner remains insufficiently understood. The aim of this study was to assess sex-specific cytokine responses and metabolic adaptation in adults with obesity and insulin resistance following a six-month weight-reduction program (WRP). Methods: Thirty-six participants (24 women and 12 men) with a value of Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) ≥ 2 underwent an individualized low-calorie diet combined with moderate physical activity and health education. Anthropometric, body composition, biochemical, oxidative stress, and cytokine parameters were evaluated before and after the intervention. Results: Both women and men showed significant reductions in body mass, Body Mass Index (BMI), waist circumference, visceral fat area (VFA), body fat mass (BFM), fasting glucose, HOMA-IR, modified Atherogenic Index of Plasma (new-AIP), malondialdehyde (MDA), and Oxidative Stress Index (OSI). Women additionally showed significant decreases in fat-free mass (FFM), skeletal-muscle mass (SMM), total body water (TBW), glycated hemoglobin A_1c (HbA1c), and triacylglycerols, whereas cholesterol in high-density lipoproteins (HDL-C) increased significantly in men. Cytokine changes were selective rather than uniform. Interleukin-1 receptor antagonist (IL-1ra), Interleukin 6 (IL-6), and Tumor Necrosis Factor alpha (TNF-α) decreased in both women and men. In sex-stratified analyses, IL-1β decreased significantly only in women, whereas IL-7 decreased significantly only in men. ClinicalTrials.gov Registration: [NCT07645105] (retrospectively registered on [11 June 2026]). Conclusions: A 6-month lifestyle-based weight-reduction program in adults with overweight or obesity and insulin resistance was associated with metabolic improvement, reduced oxidative stress, and partial attenuation of obesity-related low-grade inflammation. The observed cytokine and metabolic changes suggest sex-related patterns of immunometabolic adaptation to weight reduction. However, these findings should be interpreted cautiously because of the relatively small sex-stratified subgroups and the number of cytokine endpoints analyzed, and they require confirmation in larger, sex-balanced studies. Full article

Leucine, an essential branched-chain amino acid, serves not only as a substrate for protein synthesis but also as a key regulator of placental function and fetal development. This study investigated the effects of dietary supplementation with RP-Leu during late gestation on placental development and offspring performance in Hu sheep. Sixty twin-pregnant ewes at day 80 of pregnancy were randomly assigned to either a control group (fed a basal diet) or an RP-Leu group (fed a basal diet supplemented with 19 g/day RP-Leu). The feeding trial lasted for 60 d. The ewes were slaughtered at day 140 of gestation. Maternal slaughter traits and fetal organ weights were recorded. Blood and milk samples were collected for milk composition analysis and targeted metabolomic profiling. Leucine supplementation significantly increased the percentage of milk fat content, total solid content, and the birth weight of lambs (p < 0.05). Improvements in placental morphology and antioxidant capacity were observed, including a significant increase in cotyledon density and a significant enhancement of catalase (CAT) activity (p < 0.05). Gene expression analysis indicated that the NOS3, SLC38A1 and FABP4 genes in the placental cotyledons (p < 0.05), and the VEGFA, NOS3, SLC27A1 and FABP4 genes were significantly upregulated in the maternal caruncles (p < 0.05). Plasma metabolomic profiling revealed increased L-glutamic acid levels and alterations in several amino acids, with pathway enrichment indicating involvement in amino acid metabolism and membrane transport processes. Transcriptomic analysis identified 739 differentially expressed genes, which were mainly enriched in the PI3K/Akt signaling pathway, ECM–receptor interaction pathway, and cytokine–cytokine receptor interaction pathway. Collectively, these findings suggest that RP-Leu supplementation during late gestation may enhance offspring growth by modulating amino acid metabolism, promoting placental development, and improving placental nutrient transport capacity, thereby supporting fetal growth and development. Full article

Dysregulated lipid metabolism is a core pathogenic driver of type 2 diabetes. Honokiol (HKL), the major bioactive constituent of Magnolia officinalis, possesses anti-diabetic and lipid-regulatory properties. However, the underlying molecular mechanism remains elusive. This study investigates how HKL ameliorates high-glucose/high-fat (HGHF)-induced hepatic lipid accumulation, with a focus on the role of SIRT3-mediated deacetylation of peroxisome proliferator-activated receptor γ (PPARG). The core targets of HKL were identified through network pharmacology and molecular docking. Human hepatic MIHA cells were treated with glucose (Glu, 40 mM) and palmitic acid (0.2~0.3 mM PA) to establish a lipid accumulation model, followed by treatment with HKL (5–10 μM) with or without a confirmed selective SIRT3 inhibitor 3-(1H-1,2,3-triazol-4-yl) pyridine (3-TYP). Lipid accumulation was assessed by Oil Red O staining and by measuring triglyceride (TG) and total cholesterol (TC) levels. Protein expression and the SIRT3-PPARG interaction were analyzed by Western blot and co-immunoprecipitation (Co-IP). SIRT3 and PPARG were identified as core targets of HKL, exhibiting strong binding with calculated energies of −6.834 and −6.579 kcal/mol, respectively. In MIHA cells, HGHF (40 mM Glu + 0.2–0.3 mM PA) induced lipid accumulation, including increased lipid droplets, and elevated TG (2.5–3.2-fold) and TC (2.2–2.8-fold) contents in a dose-dependent manner, accompanied by downregulated SIRT3/PPARG expression and heightened global protein acetylation. The non-cytotoxic HGHF-M condition (40 mM Glu + 0.2 mM PA) was selected for further experiments. HKL (5–10 μM) dose-dependently reduced lipid accumulation by ~38–60%, decreased TG and TC levels by up to ~13% and ~30%, and restored SIRT3/PPARG expression. The protective effects of HKL were reversed by inhibition of SIRT3 with 3-TYP. Co-IP confirmed the interaction between SIRT3 and PPARG, and SIRT3 overexpression significantly decreased the acetylation level of PPARG. This study suggests that HKL ameliorates hepatic lipid accumulation via SIRT3-mediated deacetylation of PPARG, providing an experimental basis for considering HKL as a potential therapeutic agent against metabolic disorders. Full article

The Mediterranean diet (MedDiet) has emerged as a promising dietary strategy for the prevention and management of type 2 diabetes mellitus (T2DM). This narrative review provides a comprehensive synthesis linking the biological pathways of the MedDiet with established clinical evidence. Adherence to this traditional dietary pattern—characterized by a high intake of fiber, complex carbohydrates, antioxidants, and healthy fats—has demonstrated significant benefits in terms of glycemic control, enhanced insulin sensitivity, and overall metabolic health. Mechanistically, the review explains how the MedDiet improves health by modulating key physiological processes, including anti-inflammatory and antioxidant pathways, the regulation of branched-chain amino acid metabolism, the enhancement of short-chain fatty acid production via gut microbiota modulation, and upregulated incretin effects. Importantly, this review explains how the MedDiet complements modern medications, including glucagon-like peptide-1 (GLP-1) receptor agonists and sodium–glucose cotransporter-2 (SGLT-2) inhibitors. By integrating molecular mechanisms with human clinical outcomes, this narrative review addresses multiple aspects of the MedDiet in both the prevention and management of T2DM including glycemic control, weight management, and cardiovascular risk reduction, rendering it a valuable dietary strategy for both the prevention and treatment of this chronic condition. Full article

Chicken meat palatability is shaped by what the meat contains (e.g., intramuscular fat and fatty-acid composition), what happens to those components during storage and cooking (including oxidation and transfer into soups or meat juices), and how tastebud signaling integrates the resulting stimuli. Chicken sold in Japan as “Jidori” (premium native-line products) is often described as having a richer flavor that lingers longer than that of standard broiler chicken, and published poultry work, including reports by the author and their colleagues, has linked this phenotype to higher arachidonic acid (AA) levels in the meat; however, the mechanistic basis remains under debate and has not been overturned. In addition, intact AA is a highly hydrophobic long-chain fatty acid that partitions poorly into aqueous phases, making a direct “AA-as-tastant” mechanism unlikely. This review develops a hierarchical interpretation that separates food-level associations from tastebud mechanisms and reframes AA as a primarily downstream lipid substrate. Two complementary routes are proposed: (i) a food-chemistry route in which cooking and storage oxidation generate low-molecular-weight, water-accessible lipid-oxidation products that partition into soups, meat juices, and cooking loss, and (ii) a receptor-centered route in which kokumi-related signaling pathways, particularly those involving the calcium-sensing receptor (CaSR), amplify taste intensity, continuity, and aftertaste within tastebuds. This framework emphasizes how these routes can be linked experimentally by combining matrix/phase manipulations with targeted carbonyl profiling, fractionation–reconstitution, and pathway-perturbation assays in tastebud readouts. Overall, the model is intended to support mechanism-focused study designs beyond single-compound explanations. Full article

Background/Objectives: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), particularly semaglutide, have demonstrated efficacy for weight loss in obesity; however, up to 40% of weight lost may derive from lean body mass. The ketogenic diet independently improves insulin sensitivity and promotes fat oxidation while preserving lean tissue. This study aimed to describe changes in body composition, insulin sensitivity, and cardiometabolic markers in patients who followed a personalized ketogenic dietary protocol while receiving low-dose semaglutide over a 6-month insulin resistance reversal program. Methods: Seven analyzed adults (six female, one male) with overweight or obesity (baseline BMI 25.6–47.2 kg/m²) participated in a clinician-supervised 6-month program combining a whole-food ketogenic diet with semaglutide (≤1.0 mg/week). Body composition and fasting metabolic markers were assessed at 1, 3, and 6 months. Results: Mean total weight loss was 21.9 kg, of which a mean of 92% was attributable to BIA-estimated fat mass. Skeletal muscle mass was largely preserved as measured by BIA (mean loss 1.2 kg), and one patient gained lean tissue. Fasting insulin declined by a mean of 15.6 µIU/mL. Visceral fat decreased by a mean of 37.0%. Six of seven patients showed reductions in high-sensitivity C-reactive protein. Triglycerides decreased in six of seven patients, and HDL cholesterol increased in all seven. LDL cholesterol responses were heterogeneous. Conclusions: In this small, uncontrolled case series, combining a ketogenic diet with low-dose semaglutide was associated with substantial fat loss, apparent preservation of lean mass as measured by BIA, and improvements in insulin sensitivity and cardiometabolic markers. Because the semaglutide dose and dietary protocol were individualized to each patient’s response, the program illustrates a personalized approach to insulin resistance. These preliminary findings are hypothesis-generating and warrant confirmation in controlled prospective studies. Full article

Alzheimer’s disease (AD) and metabolic syndrome often occur together, sharing characteristics such as insulin resistance, dyslipidemia, and chronic inflammation. Metabolic dysfunction frequently precedes cognitive decline, indicating that early intervention might alter the disease’s progression. We investigated whether the GLP-1 receptor agonist semaglutide (SMGL) influences metabolic impairment and AD pathology in an AD mouse model. Male and female 5xFAD and wild-type (WT) mice on regular (RD) or high-fat diets (HFD) were administered SMGL for 13 weeks. SMGL-treated groups exhibited significant, context-dependent effects. In metabolically challenged 5xFAD HFD mice, treatment led to reduced body weight, improved glucose tolerance, normalized cholesterol levels, and a restored balance of adiponectin and leptin. These improvements were associated with reduced Aβ40 and Aβ42 levels, restored GLP-1 receptor expression, increased synaptophysin and βIII-tubulin levels, and enhanced spatial memory. SMGL also decreased Iba1 and CD68 immunoreactivity in the hippocampus and cortex, reduced macrophage infiltration, and lowered CD36 expression in visceral adipose tissue (VAT), indicating coordinated anti-inflammatory effects. WT RD mice showed minimal metabolic responses and a modest decline in Y-maze performance, suggesting that excessive GLP-1 receptor activation may disrupt neuronal homeostasis when metabolic status is normal. SMGL acts as a context-specific metabolic and neuroprotective agent, offering the greatest benefits under conditions of metabolic dysfunction. These findings in a preclinical model suggest that targeting early metabolic disturbances provides a testable hypothesis for attenuating AD-related neurodegeneration, though further translational studies are required. Full article

Leptin (LEP) is an adipocyte-derived cytokine that integrates nutritional status, metabolism, and reproduction in cattle, with particular relevance for modern high-producing dairy cows. In ruminants, LEP and its receptors are widely expressed in metabolic and reproductive tissues, including adipose tissue, liver, hypothalamus, pituitary, ovary, uterus, and placenta, where LEP modulates energy homeostasis, neuroendocrine function, and local tissue responses. Changes in circulating LEP concentrations during the transition period reflect changes in body fat reserve, insulin and GH-IGF-1 dynamics, thyroid hormones, and inflammation and contribute to coordinated metabolic adaptations supporting the onset of lactation. At the reproductive level, LEP influences the hypothalamic–pituitary–gonadal axis, affects the pulsatility of luteinizing hormone (LH) under nutritional stress, and exerts direct effects on ovarian steroidogenesis, folliculogenesis, oocyte competence, embryo development, and uterine immune function. New evidence also links LEP profiles to major peripartum disorders, including subclinical ketosis, insulin resistance, postpartum ovarian inactivity, and uterine inflammatory diseases, and emphasises its potential as part of a panel evaluating the risk of metabolic and reproductive disorders. Furthermore, polymorphisms within the bovine LEP gene and its signalling network have been associated with milk production, feed efficiency, body condition, and fertility traits, suggesting opportunities to incorporate markers into genomic selection schemes aimed at improving robustness and reproductive performance. This review summarises current knowledge on LEP biology in cattle, with an emphasis on dairy cows, and discusses perspectives on translating this information into practical tools for nutritional management, health monitoring, and genetic improvement in bovine production systems. Full article

Fatty liver disease represents a major metabolic disorder affecting domestic animals worldwide, with significant implications for animal health, welfare, and agricultural productivity. Disrupted communication between mitochondria and other organelles—particularly the endoplasmic reticulum, lipid droplets, and lysosomes—plays a critical role in disease pathogenesis. This review synthesizes knowledge on inter-organellar communication across domestic animals, with emphasis on species-specific adaptations. We address the “Dairy Cow Paradox”—periparturient dairy cows develop severe hepatic steatosis (>30% liver fat), yet under sterile conditions, they have a higher threshold for progressing to sterile steatohepatitis compared to rodents and humans. However, it is critical to note that severe fatty liver in dairy cows is indeed associated with impaired autophagy, inflammation, and liver damage, particularly when accompanied by ketosis or concurrent infections, and 39% of transition cows exhibit moderate to severe lymphocytic hepatitis. We propose that the tolerance to severe steatosis in dairy cows arises from three adaptations: (1) attenuated innate immune sensing via the cGAS-STING pathway; (2) enhanced lipid buffering from perilipin 5 (PLIN5) with a hypothesized ruminant-specific Val152 substitution that may stabilize lipid droplet–mitochondria contacts; and (3) dampened calcium signaling due to ER–mitochondria membrane lipid raft rigidity, elevated inositol 1,4,5-trisphosphate receptor 2 (IP₃R2) expression, and reduced mitochondrial calcium uniporter (MCU) conductance. We contrast this with the inflammatory steatohepatitis common in rodent models driven by calcium overload and mitochondrial DNA (mtDNA) release, and glucocorticoid-mediated mitofusin 1 (MFN1) suppression, causing mitochondrial fragmentation in poultry. We identify critical knowledge gaps, including the need to define bovine and avian mitochondria-associated endoplasmic reticulum membrane (MAM) proteomes and spatially resolve hepatic zonal communication patterns. Targeting organellar communication hubs with nutraceuticals or pharmacological agents offers promising therapeutic strategies. Full article

Background/Objectives: Obesity and menopause are major determinants of skeletal deterioration; however, their combined effects on bone remodeling and associated cellular bioenergetics remain incompletely understood. This study aimed to determine whether obesity induces osteoporotic alterations under both estrogen-replete and estrogen-deficient conditions and to evaluate the therapeutic potential of dental tissue-derived mesenchymal stem cells (D-MSCs). Methods: Female mice were subjected to ovariectomy (OVX) and/or high-fat diet (HFD) feeding for 16 weeks to establish obesity-associated osteoporosis models. D-MSCs were administered intraperitoneally at defined intervals. Body weight and serum leptin levels were measured to assess metabolic status. Femoral tissues were analyzed by quantitative real-time PCR for estrogen receptors (ERα, ERβ), inflammatory markers (Il-1β, Tnf-α), mitochondrial regulators (Pgc1α, Pgc1β), and the OPG/RANKL ratio. Histological analysis was performed to evaluate bone marrow adiposity. Results: HFD significantly increased body weight and serum leptin levels in both intact and OVX mice. Obesity was associated with reduced expression of ERα and ERβ, decreased Pgc1α levels, and a lower OPG/RANKL ratio, accompanied by increased Il-1β, Tnf-α, and Pgc1β expression. D-MSC administration attenuated body weight gain and reduced leptin levels, particularly in OVX mice. In femoral tissue, D-MSC treatment restored estrogen receptor expression, increased Pgc1α, decreased Pgc1β, and normalized the OPG/RANKL ratio. In addition, inflammatory marker expression and bone marrow adiposity were reduced following MSC administration. Conclusions: Obesity induces bone remodeling dysregulation under both intact and estrogen-deficient conditions, characterized by altered estrogen signaling, inflammatory activation, and mitochondrial imbalance. D-MSC administration was associated with partial restoration of these alterations, suggesting a potential role in modulating metabolic and skeletal homeostasis in obesity-associated bone loss. Full article

Background/Objectives: Obesity is a multifactorial chronic condition characterized by the accumulation of excess adiposity and complex interplay between intrinsic and extrinsic factors. It is an increasingly common condition, closely implicated with the incidence and progression of cardiovascular disease and its risk factors. This narrative review synthesizes and summarizes recent evidence on obesity, with a focus on the diagnosis of obesity, an exploration of both visceral and subcutaneous adipose tissue, available interventions for obesity ranging from dietary modifications to novel anti-obesity medications, and key associations with obesity and cardiovascular diseases. This review is distinct in its integrated focus on obesity definition and diagnosis, imaging modalities, the latest non-pharmacologic and pharmacologic interventions, and also the interplay between obesity and certain cardiovascular conditions as well as their risk factors. Results: The diagnosis of obesity has been evolving with the incorporation of anthropometric measurements and imaging modalities rather than simply the body mass index. There is a wide array of contributors to obesity including genetic factors, behavior, hormonal regulators, the brain–gut axis, and psychosocial stressors. Anti-obesity medications have been evolving rapidly, with current emphasis on glucagon-like peptide 1 receptor agonists. Obesity is closely implicated in cardiovascular conditions such as atherosclerotic disease, heart failure, atrial fibrillation, and hypertension as well as related risk factors such as diabetes mellitus, chronic kidney disease and sleep apnea. Conclusions: Obesity is a widely prevalent, chronic, and complex disease. The use of a variety of anthropometric measurements can help risk-stratify individuals. Imaging techniques are also helpful in evaluating body fat. Evaluating individuals from a holistic perspective is imperative to appreciate the various contributors to obesity. There are a variety of interventions available for obesity management including lifestyle interventions, bariatric surgery, and pharmacologic therapy. Notably, obesity is closely tied with cardiovascular diseases and recent pharmacologic anti-obesity agents may mitigate cardiovascular risk. Full article

The mammary gland is a heterogeneous organ that modulates ductal morphogenesis and alveolar differentiation. Obesity is a significant risk factor for several cancers, including postmenopausal breast cancer. We and others have described an association between obesity and increased breast cancer growth. However, the effects of obesity on the mammary fat pad microenvironment (MFPME) remain understudied. Here, we investigated the effect of the Western Diet (WD) on immunocompetent female mice and on their MFPME. Our data suggest that the WD increased body, liver, and perigonadal white adipose tissue (pWAT) weight, as well as myeloid cell infiltration into these tissues. Interestingly, we did not find any significant change in CD4⁺ and CD8⁺ T cells in the liver, blood, and pWAT. NanoString data demonstrates that various cellular processes, including the complement system, innate immune system, phagocytic activity, immune metabolism, and NOD-like receptor (NLR) signaling, were upregulated in the MFPME of obese mice. RNA-Seq data suggest that WD significantly modulated MFPME physiology through regulation of gene expression, cellular processes, and signaling pathways. Further investigation is necessary to determine how WD-mediated changes in MFPME modulate breast cancer biology. Full article

Objectives: Obesity and the associated metabolic dysfunction influence fertility performance at molecular levels and ABC transporters are considered as potential molecular factors affecting fertility both in the testis and sperm; therefore, we aimed to examine the effect of a short-term diet-induced obesity on testicular and spermatic ABC transporters in a rat model focusing on the expressions of P-glycoprotein (P-gp, Abcb1) and breast cancer resistance protein (BCRP, Abcg2). The testicular androgen state involving aromatase enzyme (Cyp19a1), androgen receptor (Ar), and testosterone levels were also evaluated. Methods: Obesity was induced in male Sprague Dawley rats by feeding a high-fat, high-sugar diet (HFHSD) for 10 weeks, and metabolic status was evaluated using a glucose tolerance test. The weight and size of reproductive organs were measured, and Abcb1a/1b, Abcg2, Cyp19a1, and Ar expression in testes or sperm was determined by RT-PCR and Western blotting. At the same time, testosterone levels were measured by ELISA. Results: HFHSD successfully induced higher weight gain with glucose intolerance and reduced reproductive organ size. In obese rats, testicular Abcb1a and Abcb1b mRNA and P-gp protein expression were significantly higher, whereas testicular Abcg2 mRNA levels decreased. Spermatic Abcb1a, Abcb1b and Abcg2 mRNA expression also reduced in obesity. Neither testicular testosterone concentration nor Cyp19a1 and Ar mRNA expression levels changed after the 10-week obesogenic diet compared with controls. Conclusions: Overall, our study revealed infertility-related ABC transporter changes in obese male rats, suggesting that these alterations may predispose obese males to fertility impairments, even before the obesity-induced androgen dysregulation. Full article

Background/Objectives: Glucagon-like peptide-1 receptor agonist (GLP-1RA)- and incretin-based therapies are now central to obesity management. Their clinical value, however, should be interpreted beyond total weight loss, because changes in fat mass, lean mass, physical function, and cardiometabolic risk may depend on the accompanying dietary, behavioral, and exercise co-interventions. This systematic review and meta-analysis evaluated GLP-1RA- and incretin-based therapies delivered within lifestyle interventions in adults with overweight or obesity. Methods: The protocol was registered in PROSPERO (CRD420261360837). PubMed/MEDLINE, Web of Science, Scopus, CINAHL, SPORTDiscus, and CENTRAL were searched from inception to the final search dates. Records were deduplicated in Zotero. Risk of bias was assessed using the Cochrane RoB 2 tool. Random-effects meta-analyses were estimated using restricted maximum likelihood with Hartung–Knapp adjustment when pooling was appropriate. Results: Across all database sources, 1651 records were identified. After removing 113 duplicate records and 212 records with an ineligible publication type before screening, 1326 records were screened. Seventy-seven reports were sought for retrieval, five were not retrieved, 72 were assessed at full text, and 48 reports corresponding to 35 independent parent trials or trial clusters were retained for qualitative synthesis. The primary kilogram-scale meta-analysis included eight independent comparisons and showed greater body-weight reduction with GLP-1RA/incretin-based therapy delivered within a lifestyle background than with placebo/control (mean difference [MD] −10.08 kg, 95% confidence interval [CI] −12.76 to −7.39; 95% prediction interval [PI] −17.86 to −2.29; I² = 95.6%). Percentage body-weight change was analyzed separately across 11 independent comparisons and also favored GLP-1RA/incretin-based therapy (MD −9.53 percentage points, 95% CI −11.92 to −7.14; 95% PI −17.58 to −1.48; I² = 95.4%). Conclusions: GLP-1RA- and incretin-based therapies delivered within lifestyle interventions are associated with clinically meaningful reductions in body weight in adults with overweight or obesity. Absolute and relative body-weight change metrics should remain analytically separate. The magnitude of benefit varies across trial contexts, and certainty remains limited by risk-of-bias concerns and considerable heterogeneity. Future trials should standardize the reporting of lifestyle co-interventions, body composition, adherence, physical-function outcomes, and safety monitoring. Full article