A Branched-Chain Amino Acid-Related Metabolic Signature that Differentiates Obese and Lean Humans and Contributes to Insulin Resistance

• DOI: 10.1016/j.cmet.2009.02.002
• Publication Date: 2009-04-08T09:08:30Z
• Authors: Christopher B. Ne...; Jie An; James R. Bain; Michael J. Muehlb...; Robert D. Stevens; Lillian F. Lien; Andrea M. Haqq; Svati H. Shah; Michelle Arlotto; Cris A. Slentz; James Rochon; Dianne Gallup; Olga Ilkayeva; Brett R. Wenner; William S. Yancy; Howard Eisenson; Gerald Musante; Richard S. Surwit; David S. Millington; Mark D. Butler; Laura P. Svetkey
• Keywords: Male; 0301 basic medicine; Physiology; HUMDISEASE; Mass Spectrometry; 03 medical and health sciences; Animals; Humans; Insulin; Metabolomics; Obesity; Rats, Wistar; Molecular Biology; Demography; 2. Zero hunger; 0303 health sciences; Cell Biology; Feeding Behavior; Middle Aged; Dietary Fats; Hormones; Rats; Dietary Supplements; Metabolome; Cytokines; Female; Insulin Resistance; Amino Acids, Branched-Chain

Metabolomic profiling of obese versus lean humans reveals a branched-chain amino acid (BCAA)-related metabolite signature that is suggestive of increased catabolism of BCAA and correlated with insulin resistance. To test its impact on metabolic homeostasis, we fed rats on high-fat (HF), HF with supplemented BCAA (HF/BCAA), or standard chow (SC) diets. Despite having reduced food intake and a low rate of weight gain equivalent to the SC group, HF/BCAA rats were as insulin resistant as HF rats. Pair-feeding of HF diet to match the HF/BCAA animals or BCAA addition to SC diet did not cause insulin resistance. Insulin resistance induced by HF/BCAA feeding was accompanied by chronic phosphorylation of mTOR, JNK, and IRS1Ser307 and by accumulation of multiple acylcarnitines in muscle, and it was reversed by the mTOR inhibitor, rapamycin. Our findings show that in the context of a dietary pattern that includes high fat consumption, BCAA contributes to development of obesity-associated insulin resistance.