Author
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LYNCH, CHRISTOPHER - Pennsylvania State University |
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Adams, Sean |
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Submitted to: Nature Reviews Endocrinology
Publication Type: Peer Reviewed Journal Publication Acceptance Date: 9/30/2014 Publication Date: 10/7/2014 Citation: Lynch, C.J., Adams, S.H. 2014. Branched-chain amino acids in metabolic signaling and insulin resistance. Nature Reviews Endocrinology. 10(12):723-736. doi: 10.1038/nrendo.2014.171. Interpretive Summary: Branched-chain amino acids (BCAAs) are important directly- and indirectly-acting nutrient signals. Frequently, their actions have been reported to be anti-obesity in nature, especially in rodent models. Yet, circulating BCAAs tend to be elevated in obesity, and even associated with poorer metabolic health and future insulin resistance or type 2 diabetes (T2D). A causal hypothesis linking elevated BCAAs and T2D implicates leucine’s ability to activate mTORC1 and uncouple insulin signaling at an early step. A “dysmetabolism” hypothesis posits that mito-toxic metabolite accumulations (not BCAAs per se) promote beta-cell mitochondrial dysfunction, stress signaling and apoptosis, changes associated with T2D. Alternatively, insulin resistance might promote aminoacidemia by increasing protein degradation that insulin normally suppresses, and/or eliciting an impairment of efficient BCAA oxidative metabolism in some tissues. Whether and how impaired BCAA metabolism might occur in obesity is reviewed. Research on the role of individual and model-dependent differences in BCAA metabolism is needed because BCKDHA, PPM1K, IVD and KLF15 have been designated as human disease candidate genes, and distinct phenotypes of tissue-specific branched chain ketoacid dehydrogenase complex activity have been detected in animal models of obesity and T2D. Technical Abstract: Branched-chain amino acids (BCAAs) are important directly- and indirectly-acting nutrient signals. Frequently, their actions have been reported to be anti-obesity in nature, especially in rodent models. Yet, circulating BCAAs tend to be elevated in obesity, and even associated with poorer metabolic health and future insulin resistance or type 2 diabetes (T2D). A causal hypothesis linking elevated BCAAs and T2D implicates leucine’s ability to activate mTORC1 and uncouple insulin signaling at an early step. A “dysmetabolism” hypothesis posits that mito-toxic metabolite accumulations (not BCAAs per se) promote beta-cell mitochondrial dysfunction, stress signaling and apoptosis, changes associated with T2D. Alternatively, insulin resistance might promote aminoacidemia by increasing protein degradation that insulin normally suppresses, and/or eliciting an impairment of efficient BCAA oxidative metabolism in some tissues. Whether and how impaired BCAA metabolism might occur in obesity is reviewed. Research on the role of individual and model-dependent differences in BCAA metabolism is needed because BCKDHA, PPM1K, IVD and KLF15 have been designated as human disease candidate genes, and distinct phenotypes of tissue-specific branched chain ketoacid dehydrogenase complex activity have been detected in animal models of obesity and T2D. |
