Crosstalk mechanisms between adipose and musculoskeletal metabolism in obesity and recent advances in nutritional diagnosis and treatment

Gao Xuefeng; Zhang Yuan; Zhu Cuifeng

doi:10.16689/j.cnki.cn11-9349/r.2026.01.007

PDF(2332 KB)

Electronic Journal of Metabolism and Nutrition of Cancer ›› 2026, Vol. 13 ›› Issue (1) : 38-51. DOI: 10.16689/j.cnki.cn11-9349/r.2026.01.007

Forum

Crosstalk mechanisms between adipose and musculoskeletal metabolism in obesity and recent advances in nutritional diagnosis and treatment

¹Gao Xuefeng, ²Zhang Yuan, ¹Zhu Cuifeng

Author information +

History +

Abstract

Obesity, a critical global public health challenge, transcends the traditional paradigm of energy imbalance, with its core lying in the intricate metabolic crosstalk network between adipose tissue and the musculoskeletal system. This review systematically delineates the fundamental mechanisms underlying adipose tissue dysfunction in obesity, encompassing impaired adipocyte expansion, exacerbated inflammation and fibrosis, dysregulated thermogenesis in brown adipose tissue, and disrupted inter-organ communication mediated by adipokines and exosomes. Concurrently, metabolic disturbances in skeletal muscle manifest as fiber-type switching, mitochondrial dysfunction, and suppression of the insulin signaling pathway, while bone participates in systemic energy regulation through factors such as osteocalcin. The adipose-musculoskeletal axis drives the progression of metabolic syndrome by forming a vicious cycle, orchestrated via inflammatory cascades, crosstalk among metabolic signaling pathways, and bidirectional regulation between adipokines and myokines. Nutritional intervention strategies have evolved from mere caloric restriction to multi-targeted precision regulation: time-restricted feeding, the Mediterranean diet, and supplementation with functional nutrients (e.g., ω-3 polyunsaturated fatty acids) synergistically improve body composition and metabolic health; anti-inflammatory diets and specific nutrients target inflammation and mitochondrial function; chrononutrition optimizes metabolic rhythms by synchronizing the circadian clock. Nevertheless, clinical translation still faces challenges, including addressing individual heterogeneity, developing multi-omics biomarkers, and optimizing drug-nutrition synergy. Future efforts should integrate precision nutrition, digital health technologies, and multidisciplinary management to overcome the bottlenecks in the prevention and treatment of obesity and its complications.

Key words

Obesity / Adipose-muscle-bone axis / Metabolic crosstalk / Adipokines / Myokines / Insulin resistance / Nutrition / Precision intervention

Cite this article

EndNote

Ris (Procite)

Bibtex

Download Citations

Gao Xuefeng, Zhang Yuan, Zhu Cuifeng. Crosstalk mechanisms between adipose and musculoskeletal metabolism in obesity and recent advances in nutritional diagnosis and treatment[J]. Electronic Journal of Metabolism and Nutrition of Cancer. 2026, 13(1): 38-51 https://doi.org/10.16689/j.cnki.cn11-9349/r.2026.01.007

References

[1] COLLABORATION NCDRF. Worldwide trends in underweight and obesity from 1990 to 2022: a pooled analysis of 3663 population-representative studies with 222 million children, adolescents, and adults[J]. Lancet, 2024, 403(10431):1027-1050.
[2] COLLABORATORS GBDAB. Global, regional, and national prevalence of adult overweight and obesity, 1990-2021, with forecasts to 2050: a forecasting study for the Global Burden of Disease Study 2021[J]. Lancet, 2025, 405(10481):813-838.
[3] SAKERS A, DE SIQUEIRA M K, SEALE P, et al. Adipose-tissue plasticity in health and disease[J]. Cell, 2022, 185 (3):419-446.
[4] SHEPTULINA A F, ANTYUKH K Y, KISELEV A R, et al. Possible mechanisms linking obesity, steroidogenesis, and skeletal muscle dysfunction[J]. Life (Basel), 2023, 13(6):1415.
[5] EMONT MP, JACOBS C, ESSENE AL, et al. A single-cell atlas of human and mouse white adipose tissue[J]. Nature, 2022, 603(7903):926-933.
[6] PELLEGRINELLI V, RODRIGUEZ-CUENCA S, ROUAULT C, et al. Dysregulation of macrophage PEPD in obesity determines adipose tissue fibro-inflammation and insulin resistance[J]. Nat Metab, 2022, 4(4):476-494.
[7] WANG S, CAO S, ARHATTE M, et al. Adipocyte Piezo1 mediates obesogenic adipogenesis through the FGF1/FGFR1 signaling pathway in mice[J]. Nat Commun, 2020, 11(1):2303.
[8] RASHIDI N, HARASYMOWICZ N S, SAVADIPOUR A, et al. PIEZO1-mediated mechanotransduction regulates collagen synthesis on nanostructured 2D and 3D models of fibrosis[J]. Acta Biomater, 2025, 193:242-254.
[9] OELKRUG R, POLYMEROPOULOS E T, JASTROCH M. Brown adipose tissue: physiological function and evolutionary significance[J]. J Comp Physiol B, 2015, 185(6):587-606.
[10] LAI M, ZHOU W, ZOU W, et al. Brown adipose tissue secretes OLFM4 to coordinate sensory and sympathetic innervation via Schwann cells[J]. Nat Commun, 2025, 16(1):5206.
[11] GLINIAK C M, GORDILLO R, YOUM Y H, et al. FGF21 promotes longevity in diet-induced obesity through metabolic benefits independent of growth suppression[J]. Cell Metab, 2025, 37(7):1547-1567.
[12] NGUYEN H P, YI D, LIN F, et al. Aifm2, a NADH oxidase, supports robust glycolysis and is required for cold-and diet-induced thermogenesis[J]. Mol Cell, 2020, 77(3):600-617.
[13] ABDILLAH A M, LEE J Y, LEE Y R, et al. Modulatory roles of capsaicin on thermogenesis in C2C12 myoblasts and the skeletal muscle of mice[J]. Chem Biol Interact, 2025, 407:111380.
[14] RAHBANI J F, ROESLER A, HUSSAIN M F, et al. Creatine kinase B controls futile creatine cycling in thermogenic fat[J]. Nature, 2021, 590(7846):480-485.
[15] FLACHS P, ADAMCOVA K, ZOUHAR P, et al. Induction of lipogenesis in white fat during cold exposure in mice: link to lean phenotype[J]. Int J Obes (Lond), 2017, 41(3):997-1005.
[16] GILANI A, STOLL L, HOMAN E A, et al. Adipose signals regulating distant organ health and disease[J]. Diabetes, 2024, 73(2):169-177.
[17] CHRISTOFIDES A, KONSTANTINIDOU E, JANI C, et al. The role of peroxisome proliferator-activated receptors (PPAR) in immune responses[J]. Metabolism, 2021, 114(893):154338.
[18] HELFER G, WU Q F. Chemerin: a multifaceted adipokine involved in metabolic disorders[J]. J Endocrinol, 2018, 238(2):R79-R94.
[19] SANDOVAL-BORQUEZ A, CARRION P, HERNANDEZ M P, et al. Adipose tissue dysfunction and the role of adipocyte-derived extracellular vesicles in obesity and metabolic syndrome[J]. J Endocr Soc, 2024, 8(8):bvae126.
[20] LE LAY S, SCHERER P E. Exploring adipose tissue-derived extracellular vesicles in inter-organ crosstalk: Implications for metabolic regulation and adipose tissue function[J]. Cell Rep, 2025, 44(6):115732.
[21] YU Y, DU H, WEI S, et al. Adipocyte-derived exosomal mir-27a induces insulin resistance in skeletal muscle through repression of ppargamma[J]. Theranostics, 2018, 8(8):2171-2188.
[22] HOTAMISLIGIL G S. Inflammation, metaflammation and immunometabolic disorders[J]. Nature, 2017, 542(7640):177-185.
[23] RAYEGO-MATEOS S, RODRIGUES-DIEZ R R, FERNANDEZ-FERNANDEZ B, et al. Targeting inflammation to treat diabetic kidney disease: the road to 2030[J]. Kidney Int, 2023, 103(3):282-296.
[24] GEORGAKIS M K, DE LEMOS J A, AYERS C, et al. Association of circulating monocyte chemoattractant protein-1 levels with cardiovascular mortality: a meta-analysis of population-based studies[J]. JAMA Cardiol, 2021, 6(5):587-592.
[25] GIALOURI C G, PAPPA M, EVANGELATOS G, et al. Effect of body mass index on treatment response of biologic-/targeted synthetic-DMARDs in patients with rheumatoid arthritis, psoriatic arthritis and axial spondyloarthritis. A systematic review[J]. Autoimmun Rev, 2023, 22(2):103357.
[26] GIANOPOULOS I, MANTZOROS C S, DASKALOPOULOU S S. Adiponectin and adiponectin receptors in atherosclerosis[J]. Endocr Rev, 2025, 46(25):1-25.
[27] HAGHIKIA A, ZIMMERMANN F, SCHUMANN P, et al. Propionate attenuates atherosclerosis by immune-dependent regulation of intestinal cholesterol metabolism[J]. Eur Heart J, 2022, 43(6):518-533.
[28] ZHAO S, KUSMINSKI C M, SCHERER P E. Adiponectin, leptin and cardiovascular disorders[J]. Circ Res, 2021, 128(1):136-149.
[29] FRIEDMAN J M. Leptin and the endocrine control of energy balance[J]. Nat Metab, 2019, 1:754-64.
[30] PEREIRA S, CLINE D L, GLAVAS M M, et al. Tissue-specific effects of leptin on glucose and lipid metabolism[J]. Endocr Rev, 2021, 42(1):1-28.
[31] REZVANI R, SHADMAND FOUMANI MOGHADAM M R, CIANFLONE K. Acylation stimulating protein/C3adesArg in the metabolic states: role of adipocyte dysfunction in obesity complications[J]. J Physiol, 2024, 602(5):773-790.
[32] CHEN D, CHEN Y, LIU J, et al. In situ protein corona-camouflaged supramolecular assemblies remodel thrombotic microenvironment for improved arterial homeostasis[J]. Sci Adv, 2025, 11(18):eadu6676.
[33] ROBERTS J D, VITTINGHOFF E, LU A T, et al. Epigenetic age and the risk of incident atrial fibrillation[J]. Circulation, 2021, 144(24):1899-1911.
[34] VALBUENA PEREZ J V, LINNENBERGER R, DEMBEK A, et al. Altered glucocorticoid metabolism represents a feature of macroph-aging[J]. Aging Cell, 2020, 19(6):e13156.
[35] LI X, HU S, ZHU Q, et al. Addressing the role of 11beta-hydroxysteroid dehydrogenase type 1 in the development of polycystic ovary syndrome and the putative therapeutic effects of its selective inhibition in a preclinical model[J]. Metabolism, 2021, 119(106):154749.
[36] MEEKS K A C, BENTLEY A R, GOUVEIA M H, et al. Genome-wide analyses of multiple obesity-related cytokines and hormones informs biology of cardiometabolic traits[J]. Genome Med, 2021, 13(1):156.
[37] NEWSOME P N, AMBERY P. Incretins (GLP-1 receptor agonists and dual/triple agonists) and the liver[J]. J Hepatol, 2023, 79(6):1557-1565.
[38] MOLANI-GOL R, RAFRAF M, ASGHARI JAFARABADI M, et al. The interaction of vitamin D supplementation with Omentin-1 gene polymorphism on metabolic factors and anthropometric indices in women with prediabetes: a study protocol for a double-blind randomized controlled trial[J]. BMC Complement Med Ther, 2025, 25(1):299.
[39] DAMER A, EL MENIAWY S, MCPHERSON R, et al. Association of muscle fiber type with measures of obesity: a systematic review[J]. Obes Rev, 2022, 23(7):e13444.
[40] WANG Y, XIE H, LIU Q, et al. Kdm2a inhibition in skeletal muscle improves metabolic flexibility in obesity[J]. Nat Metab, 2025, 7(2):383-400.
[41] MENGESTE A M, RUSTAN A C, LUND J. Skeletal muscle energy metabolism in obesity[J]. Obesity (Silver Spring), 2021, 29(10):1582-1595.
[42] 吴菊花, 杨亚南, 翁锡全, 等. 低氧运动干预营养性肥胖模型大鼠骨骼肌能量代谢的变化[J]. 中国组织工程研究, 2022, 26(29):4598-4604.
[43] PILEGGI C A, HOOKS B G, MCPHERSON R, et al. Targeting skeletal muscle mitochondrial health in obesity[J]. Clin Sci (Lond), 2022, 136(14):1081-1110.
[44] XIA W, VEERAGANDHAM P, CAO Y, et al. Obesity causes mitochondrial fragmentation and dysfunction in white adipocytes due to RalA activation[J]. Nat Metab, 2024, 6(2):273-289.
[45] YAO T, YAN H, ZHU X, et al. Obese skeletal muscle-expressed interferon regulatory factor 4 transcriptionally regulates mitochondrial branched-chain aminotransferase reprogramming metabolome[J]. Diabetes, 2022, 71(11):2256-2271.
[46] MAO H, LI L, FAN Q, et al. Endothelium-specific depletion of LRP1 improves glucose homeostasis through inducing osteocalcin[J]. Nat Commun, 2021, 12(1):5296.
[47] SYLOW L, TOKARZ V L, RICHTER E A, et al. The many actions of insulin in skeletal muscle, the paramount tissue determining glycemia[J]. Cell Metab, 2021, 33(4):758-780.
[48] MOSIALOU I, SHIKHEL S, LIU J M, et al. MC4R-dependent suppression of appetite by bone-derived lipocalin 2[J]. Nature, 2017, 543(7645):385-390.
[49] ALLERTON T D, KOWALSKI G M, STAMPLEY J, et al. An ethanolic extract of artemisia dracunculus l. Enhances the metabolic benefits of exercise in diet-induced obese mice[J]. Med Sci Sports Exerc, 2021, 53(4):712-723.
[50] JIN L, HAN S, LV X, et al. The muscle-enriched myokine Musclin impairs beige fat thermogenesis and systemic energy homeostasis via Tfr1/PKA signaling in male mice[J]. Nat Commun, 2023, 14(1):4257.
[51] LI T, ZHAO H, GUO G, et al. VMP1 affects endoplasmic reticulum stress sensitivity via differential modulation of the three unfolded protein response arms[J]. Cell Rep, 2023, 42(3):112209.
[52] ZHANG J, ACOSTA F M, WANG X, et al. Osteocyte connexin hemichannels and prostaglandin E(2) release dictate bone marrow mesenchymal stromal cell commitment[J]. Proc Natl Acad Sci U S A, 2025, 122(7):e2412144122.
[53] OGURI Y, SHINODA K, KIM H, et al. CD81 controls beige fat progenitor cell growth and energy balance via FAK signaling[J]. Cell, 2020, 182(3):563-577.
[54] SOTAK M, CLARK M, SUUR B E, et al. Inflammation and resolution in obesity[J]. Nat Rev Endocrinol, 2025, 21(1):45-61.
[55] NASH D, HUGHES M G, BUTCHER L, et al. IL-6 signaling in acute exercise and chronic training: Potential consequences for health and athletic performance[J]. Scand J Med Sci Sports, 2023, 33(10):4-19.
[56] STOHR O, TAO R, MIAO J, et al. FoxO1 suppresses Fgf21 during hepatic insulin resistance to impair peripheral glucose utilization and acute cold tolerance[J]. Cell Rep, 2021, 34(12):108893.
[57] FERACO A, GORINI S, ARMANI A, et al. Exploring the role of skeletal muscle in insulin resistance: lessons from cultured cells to animal models[J]. Int J Mol Sci,2021,22(17):9327.
[58] YOSHINO M, YOSHINO J, KAYSER B D, et al. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women[J]. Science, 2021, 372(6547):1224-1229.
[59] ZHOU M, WEI Y, FENG Y, et al. Arginine regulates skeletal muscle fiber type formation via mTor signaling pathway[J]. Int J Mol Sci, 2024, 25(11):6184.
[60] ABOU DAHER A, ALKHANSA S, AZAR W S, et al. Translational aspects of the mammalian target of rapamycin complexes in diabetic nephropathy[J]. Antioxid Redox Signal, 2022, 37(49):802-819.
[61] DE CABO R, MATTSON M P. Effects of intermittent fasting on health, aging, and disease[J]. N Engl J Med, 2019, 382(18):2541-2551.
[62] HEPLER C, WEIDEMANN B J, WALDECK N J, et al. Time-restricted feeding mitigates obesity through adipocyte thermogenesis[J]. Science, 2022, 378(6617):276-284.
[63] DEOTA S, LIN T, CHAIX A, et al. Diurnal transcriptome landscape of a multi-tissue response to time-restricted feeding in mammals[J]. Cell Metab, 2023, 35(1):150-165.
[64] CHEN J, XIANG J, ZHOU M, et al. Dietary timing enhances exercise by modulating fat-muscle crosstalk via adipocyte AMPKalpha2 signaling[J]. Cell Metab, 2025, 37(6):1364-1380.
[65] KONIECZNA J, RUIZ-CANELA M, GALMES-PANADES A M, et al. An energy-reduced mediterranean diet, physical activity, and body composition: an interim subgroup analysis of the predimed-plus randomized clinical trial[J]. JAMA Netw Open, 2023, 6(10):e2337994.
[66] BERGOUIGNAN A, MOMKEN I, SCHOELLER D A, et al. Metabolic fate of saturated and monounsaturated dietary fats: the Mediterranean diet revisited from epidemiological evidence to cellular mechanisms[J]. Prog Lipid Res, 2009, 48(3-4):128-147.
[67] MA Y, SUN Y, SUN L, et al. Effects of gut microbiota and fatty acid metabolism on dyslipidemia following weight-loss diets in women: Results from a randomized controlled trial[J]. Clin Nutr, 2021, 40(11):5511-5520.
[68] LI L, LI R, TIAN Q, et al. Effects of healthy low-carbohydrate diet and time-restricted eating on weight and gut microbiome in adults with overweight or obesity: feeding RCT[J]. Cell Rep Med, 2024, 5(11):101801.
[69] KAHLEOVA H, PETERSEN K F, SHULMAN G I, et al. Effect of a low-fat vegan diet on body weight, insulin sensitivity, postprandial metabolism, and intramyocellular and hepatocellular lipid levels in overweight adults: a randomized clinical trial[J]. JAMA Netw Open, 2020, 3(11):e2025454.
[70] CALDER P C. Dietary factors and low-grade inflammation in relation to overweight and obesity revisted[J]. Br J Nutr, 2022, 127(10):1455-1457.
[71] LIU X, XU M, WANG H, et al. Role and mechanism of short-chain fatty acids in skeletal muscle homeostasis and exercise performance[J]. Nutrients, 2025, 17(9):1463.
[72] CIPRIANI C, PEPE J, PIEMONTE S, et al. Vitamin D and its relationship with obesity and muscle[J]. Int J Endocrinol, 2014, 2014(4482):841248.
[73] ABBAS M A. Physiological functions of Vitamin D in adipose tissue[J]. J Steroid Biochem Mol Biol, 2017, 165(Pt B):369-381.
[74] PROVVISIERO D P, NEGRI M, AMATRUDO F, et al. 1,25Dihydroxyvitamin D3 mitigates the adipogenesis induced by bisphenol A in 3T3-L1 and hAMSC through miR-27-3p regulation[J]. Int J Obes (Lond), 2024, 48(12):1793-1802.
[75] ZHAO Y, QIN R. Vitamin D3 affects browning of white adipocytes by regulating autophagy via PI3K/Akt/mTOR/p53 signaling in vitro and in vivo[J]. Apoptosis, 2022, 27(2):992-1003.
[76] BARBAGALLO M, VERONESE N, DOMINGUEZ L J. Magnesium in type 2 diabetes mellitus, obesity, and metabolic syndrome[J]. Nutrients, 2022, 14(3):714.
[77] ASKARI M, MOZAFFARI H, JAFARI A, et al. The effects of magnesium supplementation on obesity measures in adults: a systematic review and dose-response meta-analysis of randomized controlled trials[J]. Crit Rev Food Sci Nutr, 2021, 61(11):2921-2937.
[78] PAN X, YE L, GUO X, et al. Glutamine production by glul promotes thermogenic adipocyte differentiation through prdm9-mediated H3K4me3 and transcriptional reprogramming[J]. Diabetes, 2023, 72(11):1574-1596.
[79] PETRUS P, LECOUTRE S, DOLLET L, et al. Glutamine links obesity to inflammation in human white adipose tissue[J]. Cell Metab, 2020, 31(2):375-390.
[80] RODRIGUES JUNIOR C F, MURATA G M, GERLINGER-ROMERO F, et al. Changes in skeletal muscle protein metabolism signaling induced by glutamine supplementation and exercise[J]. Nutrients, 2023, 15(22):4711.
[81] ANDERSSON L E, SHCHERBINA L, AL-MAJDOUB M, et al. Glutamine-elicited secretion of glucagon-like peptide 1 is governed by an activated glutamate dehydrogenase[J]. Diabetes, 2018, 67(3):372-384.
[82] JERAB D, BLANGERO F, DA COSTA P C T, et al. Beneficial effects of omega-3 fatty acids on obesity and related metabolic and chronic inflammatory diseases[J]. Nutrients, 2025, 17(7):1253.
[83] DAO M C, EVERARD A, ARON-WISNEWSKY J, et al. Akkermansia muciniphila and improved metabolic health during a dietary intervention in obesity: relationship with gut microbiome richness and ecology[J]. Gut, 2016, 65(3):426-436.
[84] CHORNER Z, BARBEAU P A, CASTELLANI L, et al. Dietary alpha-linolenic acid supplementation alters skeletal muscle plasma membrane lipid composition, sarcolemmal FAT/CD36 abundance, and palmitate transport rates[J]. Am J Physiol Regul Integr Comp Physiol, 2016, 311(6):R1234-1242.
[85] 白晓琳, 薄钰莹, 丁宁, 等. 南极磷虾油、鱼油与花生四烯酸油对骨质疏松症小鼠脂质代谢的影响[J]. 食品科学, 2022, 43(17):131-137.
[86] BRENNAN L, HU F B, SUN Q. Metabolomics meets nutritional epidemiology: harnessing the potential in metabolomics data[J]. Metabolites, 2021, 11(10):709.
[87] BEN-YACOV O, GODNEVA A, REIN M, et al. Gut microbiome modulates the effects of a personalised postprandial-targeting (PPT) diet on cardiometabolic markers: a diet intervention in pre-diabetes[J]. Gut, 2023, 72(8):1486-1496.
[88] BERRY S E, VALDES A M, DREW D A, et al. Human postprandial responses to food and potential for precision nutrition[J]. Nat Med, 2020, 26(6):964-973.
[89] MARTENS T, BECK R W, BAILEY R, et al. Effect of continuous glucose monitoring on glycemic control in patients with type 2 diabetes treated with basal insulin: a randomized clinical trial[J]. JAMA, 2021, 325(22):2262-2272.
[90] SPRING B, PFAMMATTER A F, SCANLAN L, et al. An adaptive behavioral intervention for weight loss management: a randomized clinical trial[J]. JAMA, 2024, 332(1):21-30.
[91] LUDVIK B, GIORGINO F, JODAR E, et al. Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes (SURPASS-3): a randomised, open-label, parallel-group, phase 3 trial[J]. Lancet, 2021, 398(10300):583-598.
[92] NILSSON M I, XHUTI D, DE MAAT N M, et al. Obesity and metabolic disease impair the anabolic response to protein supplementation and resistance exercise: a retrospective analysis of a randomized clinical trial with implications for aging, sarcopenic obesity, and weight management[J]. Nutrients, 2024, 16(24):4407.
[93] KLINC A, GROSELJ U, MLINARIC M, et al. Case report: The success of empagliflozin therapy for glycogen storage disease type 1b[J]. Front Endocrinol (Lausanne) 2024;15:1365700.
[94] XIE Z, ZHENG G, LIANG Z, et al. Seven glucagon-like peptide-1 receptor agonists and polyagonists for weight loss in patients with obesity or overweight: an updated systematic review and network meta-analysis of randomized controlled trials[J]. Metabolism, 2024, 161:156038.