{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T09:52:21Z","timestamp":1791625941959,"version":"4.3.4"},"reference-count":286,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,8,30]],"date-time":"2025-08-30T00:00:00Z","timestamp":1756512000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Slovenian Research and Innovation Agency (ARIS), Slovenia","award":["P3-0043"],"award-info":[{"award-number":["P3-0043"]}]},{"name":"Slovenian Research and Innovation Agency (ARIS), Slovenia","award":["N3-0256"],"award-info":[{"award-number":["N3-0256"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Background\/Objectives: Obesity and type 2 diabetes mellitus (T2DM) profoundly disrupt lipid metabolism within local microenvironments of skeletal muscle and its associated connective tissues, including adipose tissue, bone, and fascia. However, the role of local communication between skeletal muscle and its proximal connective tissues in propagating metabolic dysfunction is incompletely understood. This narrative review synthesizes current evidence on these local metabolic interactions, highlighting novel insights and existing gaps. Methods: We conducted a comprehensive literature analysis of primary research published in the last decade, sourced from PubMed, Web of Science, and ScienceDirect. Studies were selected for relevance to skeletal muscle, adipose tissue, fascia, and bone lipid metabolism in the context of obesity and T2DM, with emphasis on molecular, cellular, and paracrine mechanisms of local crosstalk. Findings were organized into thematic sections addressing physiological regulation, pathological remodeling, and inter-organ signaling pathways. Results: Our synthesis reveals that local lipid dysregulation in obesity and T2DM involves altered fatty acid transporter dynamics, mitochondrial overload, fibro-adipogenic remodeling, and compartment-specific adipose tissue dysfunction. Crosstalk via myokines, adipokines, osteokines, bioactive lipids, and exosomal miRNAs integrates metabolic responses across these tissues, amplifying insulin resistance and lipotoxic stress. Emerging evidence highlights the underappreciated roles of fascia and marrow adipocytes in regional lipid handling. Conclusions: Collectively, these insights underscore the pivotal role of inter-tissue crosstalk among skeletal muscle, adipose tissue, bone, and fascia in orchestrating lipid-induced insulin resistance, and highlight the need for integrative strategies that target this multicompartmental network to mitigate metabolic dysfunction in obesity and T2DM.<\/jats:p>","DOI":"10.3390\/metabo15090581","type":"journal-article","created":{"date-parts":[[2025,9,2]],"date-time":"2025-09-02T13:01:13Z","timestamp":1756818073000},"page":"581","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Crosstalk Between Skeletal Muscle and Proximal Connective Tissues in Lipid Dysregulation in Obesity and Type 2 Diabetes"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3429-4441","authenticated-orcid":false,"given":"Nata\u0161a","family":"Pollak","sequence":"first","affiliation":[{"name":"Institute of Anatomy, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-4414-6667","authenticated-orcid":false,"given":"Efua Gyakye","family":"Jane\u017ei\u010d","sequence":"additional","affiliation":[{"name":"Institute of Anatomy, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2454-6592","authenticated-orcid":false,"given":"\u017diga","family":"\u0160ink","sequence":"additional","affiliation":[{"name":"Institute of Anatomy, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiedozie Kenneth","family":"Ugwoke","sequence":"additional","affiliation":[{"name":"Institute of Anatomy, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1016\/S0140-6736(25)00397-6","article-title":"Global, Regional, and National Prevalence of Adult Overweight and Obesity, 1990\u20132021, with Forecasts to 2050: A Forecasting Study for the Global Burden of Disease Study 2021","volume":"405","author":"Kerr","year":"2025","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"109119","DOI":"10.1016\/j.diabres.2021.109119","article-title":"IDF Diabetes Atlas: Global, Regional and Country-Level Diabetes Prevalence Estimates for 2021 and Projections for 2045","volume":"183","author":"Sun","year":"2022","journal-title":"Diabetes Res. 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