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With time, these disturbances lead to the development of progressive disease and end-organ involvement. However, the influence of cholecalciferol on metabolic pathways as a possible mechanism of its immunomodulatory activity in obesity-related hypertension is not known. In a phase 2, randomized, single-center, 24-week trial, we evaluated, as a secondary outcome, the serum metabolome of 36 age- and gender-matched adults with obesity-related hypertension and vitamin D deficiency, before and after supplementation with cholecalciferol therapy along with routine medication. The defined endpoint was the assessment of circulating metabolites using a nuclear magnetic resonance-based metabolomics approach. Univariate and multivariate analyses were used to evaluate the systemic metabolic alterations caused by cholecalciferol. In comparison with normotensive controls, hypertensive patients presented overall decreased expression of several amino acids (p &lt; 0.05), including amino acids with ketogenic and glucogenic properties as well as aromatic amino acids. Following cholecalciferol supplementation, increases were observed in glutamine (p &lt; 0.001) and histidine levels (p &lt; 0.05), with several other amino acids remaining unaffected. Glucose (p &lt; 0.05) and acetate (p &lt; 0.05) decreased after 24 weeks in the group taking the supplement, and changes in the saturation of fatty acids (p &lt; 0.05) were also observed, suggesting a role of liposoluble vitamin D in lipid metabolism. Long-term cholecalciferol supplementation in chronically obese and overweight hypertensives induced changes in the blood serum metabolome, which reflected systemic metabolism and may have fostered a new microenvironment for cell proliferation and biology. Of note, the increased availability of glutamine may be relevant for the proliferation of different T-cell subsets.<\/jats:p>","DOI":"10.3390\/ijms25063416","type":"journal-article","created":{"date-parts":[[2024,3,18]],"date-time":"2024-03-18T06:58:39Z","timestamp":1710745119000},"page":"3416","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Standard Doses of Cholecalciferol Reduce Glucose and Increase Glutamine in Obesity-Related Hypertension: Results of a Randomized Trial"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4386-6026","authenticated-orcid":false,"given":"Catarina","family":"Santos","sequence":"first","affiliation":[{"name":"Health Sciences Faculty, University of Beira Interior, 6200-505 Covilh\u00e3, Portugal"},{"name":"Nephrology Department, Castelo Branco Local Health Unit, 6000-128 Castelo Branco, Portugal"}]},{"given":"Rui","family":"Carvalho","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, 3000-456 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1118-5525","authenticated-orcid":false,"given":"Ana Mafalda","family":"Fonseca","sequence":"additional","affiliation":[{"name":"CICS-UBI, Investigation Center for Health Sciences, University of Beira Interior, 6200-505 Covilh\u00e3, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6191-5912","authenticated-orcid":false,"given":"Miguel","family":"Castelo Branco","sequence":"additional","affiliation":[{"name":"Health Sciences Faculty, University of Beira Interior, 6200-505 Covilh\u00e3, Portugal"},{"name":"CICS-UBI, Investigation Center for Health Sciences, University of Beira Interior, 6200-505 Covilh\u00e3, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7635-783X","authenticated-orcid":false,"given":"Marco","family":"Alves","sequence":"additional","affiliation":[{"name":"Laboratory of Endocrine and Metabolic Research, UMIB\u2014Unit for Multidisciplinary Research in Biomedicine, ICBAS\u2014School of Medicine and Biomedical Sciences, University of Porto, 4050-313 Porto, Portugal"},{"name":"Laboratory for Integrative and Translational Research in Population Health (ITR), University of Porto, 4200-465 Porto, Portugal"},{"name":"Laboratory of Physiology, Department of Immuno-Physiology and Pharmacology, ICBAS\u2014School of Medicine and Biomedical Sciences, University of Porto, 4050-313 Porto, Portugal"}]},{"given":"Ivana","family":"Jarak","sequence":"additional","affiliation":[{"name":"Laboratory of Drug Development and Technologies, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"i3S-Institute for Investigation and Health Innovation, University of Porto, 4200-393 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2028","DOI":"10.1111\/bph.14436","article-title":"Hypertension: A new treatment for an old disease? 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