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Here, we asked if the defective carbohydrate metabolism alters the fat utilization by the skeletal muscles of vdr<jats:sup>\u2212\/\u2212<\/jats:sup> mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To check the effect of high\u2010fat\u2010containing diets on muscle mass and metabolism of vdr<jats:sup>\u2212\/\u2212<\/jats:sup> mice, we subjected them to two different milk fat\u2010based diets (milk fat diet with 60% of energy from milk fat and milk\u2010based diet [MBD] with 37% of energy from milk fat) and lard\u2010based high\u2010fat diet (HFD) containing 60% of energy from lard fat. Skeletal muscles and pancreas from these mice were analysed using RNA sequencing, quantitative reverse transcription polymerase chain reaction and western blot to understand the changes in signalling and metabolic pathways. Microscopic analyses of cryosections stained with haematoxylin and eosin, BODIPY, succinate dehydrogenase and periodic acid\u2013Schiff reagent were performed to understand changes in morphology and metabolism of muscle fibres and pancreatic islets.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Transcriptomic analyses showed that the skeletal muscles of vdr<jats:sup>\u2212\/\u2212<\/jats:sup> mice exhibit upregulation of the fatty acid oxidation pathways, suggesting a shift towards increased lipid utilization even in a carbohydrate\u2010enriched regular chow diet (chow). Two different milk fat\u2010enriched diets restored body weight (12.01\u00a0\u00b1\u00a00.33\u00a0g in chow\u00a0vs. 17.99\u00a0\u00b1\u00a00.62\u00a0g in MBD) and muscle weights (38.58\u00a0\u00b1\u00a03.84\u00a0mg in chow vs. 110.72\u00a0\u00b1\u00a01.96\u00a0mg in MBD for gastrocnemius [GAS]) of vdr<jats:sup>\u2212\/\u2212<\/jats:sup> mice. Muscle ATP levels (0.56\u00a0\u00b1\u00a00.18\u00a0\u03bcmol in chow vs. 1.48\u00a0\u00b1\u00a00.08\u00a0\u03bcmol in MBD) and protein synthesis (0.25\u00a0\u00b1\u00a00.04\u00a0A.U. in chow vs. 2.02\u00a0\u00b1\u00a00.06\u00a0A.U. in MBD) were upregulated by MBD. However, despite increasing muscle energy levels, HFD failed to restore the muscle mass and cross\u2010sectional area to that of wild\u2010type (WT) mice (104.95\u00a0\u00b1\u00a02.6\u00a0mg for WT mice on chow vs. 77.26\u00a0\u00b1\u00a01.7\u00a0mg for vdr<jats:sup>\u2212\/\u2212<\/jats:sup> mice on HFD for GAS). Moreover, HFD disrupted glucose homeostasis in vdr<jats:sup>\u2212\/\u2212<\/jats:sup> mice, while MBD restored it. We further analysed insulin response and pancreatic insulin levels of these mice to show that HFD led to reduced insulin levels in pancreatic beta cells of vdr<jats:sup>\u2212\/\u2212<\/jats:sup> mice (mean intensity of 1.5\u00a0\u00d7\u00a010<jats:sup>\u22128<\/jats:sup> for WT mice on chow vs. 4.3\u00a0\u00d7\u00a010<jats:sup>\u22129<\/jats:sup> for vdr<jats:sup>\u2212\/\u2212<\/jats:sup> mice on HFD). At the same time, MBD restored glucose\u2010stimulated pancreatic insulin response (mean intensity of 9.2\u00a0\u00d7\u00a010<jats:sup>\u22129<\/jats:sup>).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Skeletal muscles of vdr<jats:sup>\u2212\/\u2212<\/jats:sup> mice are predisposed to utilize fatty acids as their primary energy source to circumvent their defective carbohydrate utilization. Thus, HFDs could restore energy levels in the skeletal muscles of vdr<jats:sup>\u2212\/\u2212<\/jats:sup> mice. This study reveals that when mice are subjected to a lard\u2010based HFD, VDR signalling is essential for maintaining insulin levels in pancreatic islets. Our data show a critical role of VDR in muscle metabolic flexibility and pancreatic insulin response.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.13378","type":"journal-article","created":{"date-parts":[[2023,12,2]],"date-time":"2023-12-02T19:50:21Z","timestamp":1701546621000},"page":"67-80","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Lack of vitamin D signalling shifts skeletal muscles towards oxidative metabolism"],"prefix":"10.1002","volume":"15","author":[{"given":"Anamica","family":"Das","sequence":"first","affiliation":[{"name":"Molecular Genetics Laboratory National Institute of Immunology  New Delhi India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neha","family":"Jawla","sequence":"additional","affiliation":[{"name":"Molecular Genetics Laboratory National Institute of Immunology  New Delhi 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