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<p>This review advances a framework that moves beyond an “ultrainsulinocentric” view of chromium(III) (CrIII) in obesity toward an integrated model centered on mitochondrial energy sensing, redox homeostasis, and inflammatory regulation. Obesity is now recognized as a systemic disorder marked by chronic low-grade inflammation and metabolic dysregulation driven by impaired AMPK activity, disrupted Nrf2/HO-1 signaling, and persistent NF-κB–mediated metaflammation. Traditional models that depict CrIII as a direct enhancer of insulin signaling are insufficient to account for its disputed essentiality, variable clinical efficacy, and emerging toxicological concerns. We synthesize mechanistic, toxicological, and clinical evidence, emphasizing ATP synthase-AMPK signaling, Nrf2/HO-1 activation, NF-κB inhibition, and classical insulin pathways in obesity, type 2 diabetes, and nonalcoholic fatty liver disease. Experimental data suggest that CrIII may accumulate within mitochondria, partially inhibit ATP synthase, and activate AMPK, thereby enhancing fatty acid oxidation and limiting lipogenesis. Concurrently, CrIII appears to strengthen antioxidant defenses and suppress inflammatory signaling, indirectly improving insulin sensitivity. Some clinical trials report modest improvements in glycemic and inflammatory markers, with substantial heterogeneity related to phenotype, formulation, dose, and duration. We propose that CrIII acts as a context-dependent modulator of the energy-redox-inflammation axis. Current clinical evidence remains insufficient to validate this mechanistic framework; future biomarker-driven, phenotype-stratified trials are required to determine whether modulation of these pathways mediates clinical benefit.</p> Graphical Abstract <p></p>

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Chromium(III) Beyond Insulin: A Mechanistic Roadmap Across the Energy–Redox–Inflammation Triad in Obesity and Cardiometabolic Disease

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月25日

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  • Mehmet Tuzcu,
  • Ramazan Ozmen,
  • Kazim Sahin

摘要

This review advances a framework that moves beyond an “ultrainsulinocentric” view of chromium(III) (CrIII) in obesity toward an integrated model centered on mitochondrial energy sensing, redox homeostasis, and inflammatory regulation. Obesity is now recognized as a systemic disorder marked by chronic low-grade inflammation and metabolic dysregulation driven by impaired AMPK activity, disrupted Nrf2/HO-1 signaling, and persistent NF-κB–mediated metaflammation. Traditional models that depict CrIII as a direct enhancer of insulin signaling are insufficient to account for its disputed essentiality, variable clinical efficacy, and emerging toxicological concerns. We synthesize mechanistic, toxicological, and clinical evidence, emphasizing ATP synthase-AMPK signaling, Nrf2/HO-1 activation, NF-κB inhibition, and classical insulin pathways in obesity, type 2 diabetes, and nonalcoholic fatty liver disease. Experimental data suggest that CrIII may accumulate within mitochondria, partially inhibit ATP synthase, and activate AMPK, thereby enhancing fatty acid oxidation and limiting lipogenesis. Concurrently, CrIII appears to strengthen antioxidant defenses and suppress inflammatory signaling, indirectly improving insulin sensitivity. Some clinical trials report modest improvements in glycemic and inflammatory markers, with substantial heterogeneity related to phenotype, formulation, dose, and duration. We propose that CrIII acts as a context-dependent modulator of the energy-redox-inflammation axis. Current clinical evidence remains insufficient to validate this mechanistic framework; future biomarker-driven, phenotype-stratified trials are required to determine whether modulation of these pathways mediates clinical benefit.

Graphical Abstract