Branched-chain amino acid catabolism rather than amino acids plasma concentrations is associated with diet-induced changes in insulin resistance in overweight to obese individuals

Haufe, Sven; Engeli, Stefan; Kaminski, Jakob; Witt, Henning; Rein, Dietrich; Kamlage, Beate; Utz, Wolfgang; Fuhrmann, Jens C.; Haas, Verena; Mähler, Anja; Schulz‐Menger, Jeanette; Luft, Friedrich C.; Boschmann, Michael; Jordan, Jens

doi:10.1016/j.numecd.2017.07.001

Cited by 39 publications

(28 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, multiadjusted logistic regression analysis showed that 3-HIB, but not valine, was independently associated with type 2 diabetes in a multivariable setting. This indicates, as recently suggested (25), that measurement of circulating 3-HIB may capture altered insulin resistance-related cellular processes more directly than circulating BCAAs-in this case, valine. Interestingly, we also found that 3-HIB increased transiently 1 week after bariatric surgery, a treatment that acutely increases insulin sensitivity (34).…”

Section: Discussionsupporting

confidence: 65%

“…3-HIB was first linked to diabetes in 1989, when higher plasma concentrations of 3-HIB were reported in individuals with type 1 diabetes, especially after fasting, with 3-HIB concentrations ranging from 20 to 100 mmol/L (21). More recently, studies have linked elevated circulating levels of 3-HIB to insulin resistance and risk of incident type 2 diabetes and gestational diabetes mellitus (22)(23)(24)(25). In contrast to CoA-bound catabolites from leucine and isoleucine degradation, 3-HIB-CoA is exclusively formed from valine breakdown and hydrolyzed by the rate-limiting enzyme 3-hydroxyisobutyryl-CoA hydrolase (HIBCH), allowing free 3-HIB to leave the mitochondria and enter the extracellular fluid (26).…”

mentioning

confidence: 99%

See 1 more Smart Citation

3-Hydroxyisobutyrate, A Strong Marker of Insulin Resistance in Type 2 Diabetes and Obesity That Modulates White and Brown Adipocyte Metabolism

et al. 2020

View full text Add to dashboard Cite

Circulating branched-chain amino acids (BCAAs) associate with insulin resistance and type 2 diabetes. 3-Hydroxyisobutyrate (3-HIB) is a catabolic intermediate of the BCAA valine. In this study, we show that in a cohort of 4,942 men and women, circulating 3-HIB is elevated according to levels of hyperglycemia and established type 2 diabetes. In complementary cohorts with measures of insulin resistance, we found positive correlates for circulating 3-HIB concentrations with HOMA2 of insulin resistance, as well as a transient increase in 3-HIB followed by a marked decrease after bariatric surgery and weight loss. During differentiation, both white and brown adipocytes upregulate BCAA utilization and release increasing amounts of 3-HIB. Knockdown of the 3-HIB-forming enzyme 3-hydroxyisobutyryl-CoA hydrolase decreases release of 3-HIB and lipid accumulation in both cell types. Conversely, addition of 3-HIB to white and brown adipocyte cultures increases fatty acid uptake and modulated insulin-stimulated glucose uptake in a time-dependent manner. Finally, 3-HIB treatment decreases mitochondrial oxygen consumption and generation of reactive oxygen species in white adipocytes, while increasing these measures in brown adipocytes. Our data establish 3-HIB as a novel adipocyte-derived regulator of adipocyte subtypespecific functions strongly linked to obesity, insulin resistance, and type 2 diabetes.

show abstract

Section: Discussionsupporting

confidence: 65%

mentioning

confidence: 99%

3-Hydroxyisobutyrate, A Strong Marker of Insulin Resistance in Type 2 Diabetes and Obesity That Modulates White and Brown Adipocyte Metabolism

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Elevated circulating BCKAs have been reported by a few studies (39,88) in rodent models of DIO. In overweight and obese individuals, lower circulating levels of the valine catabolite, 3-HIB, and not BCAAs, were associated with the metabolic improvements following weight loss (164) and were also correlated with insulin-stimulated glucose disposal in older obese women (133). Interestingly, elevated BAIBA levels due to enhanced valine catabolism were also demonstrated to be inversely correlated with fasting glucose, insulin, HOMA-IR, triglycerides, and total cholesterol in a random large human cohort enrolled in the longitudinal Framingham Heart Study (117).…”

Section: Obesity and Irmentioning

confidence: 94%

Role of branched‐chain amino acid–catabolizing enzymes in intertissue signaling, metabolic remodeling, and energy homeostasis

2019

View full text Add to dashboard Cite

Beyond their contribution as fundamental building blocks of life, branched‐chain amino acids (BCAAs) play a critical role in physiologic and pathologic processes. Importantly, BCAAs are associated with insulin resistance, obesity, cardiovascular disease, and genetic disorders. However, several metabolome‐wide studies in recent years could not attribute alterations in systemic BCAAs as the sole driver of endocrine perturbations, suggesting that a snapshot of global BCAA changes does not always reveal the underlying modifications. Because enzymes catabolizing BCAAs have a unique distribution, it is plausible that the tissue‐specific roles of BCAA‐catabolic enzymes could precipitate changes in systemic BCAA levels, flux, and action. We review the genetic and pharmacological approaches dissecting the role of BCAA‐catabolic enzyme dysfunctions. We summarized emerging evidence on BCAA metabolic intermediates, tissue specificity of BCAA‐catabolizing enzymes, and crosstalk between different metabolites in driving metabolic maladaptation in health and pathology. This review substantiates the understanding that tissue‐specific dysfunction of the BCAA‐catabolic enzymes and accumulating intermediary metabolites could act as better surrogates of metabolic imbalances, highlighting the biochemical communication among the nutrient triad of BCAAs, glucose, and fatty acid.—Biswas, D., Duffley, L., Pulinilkunnil, T. Role of branched‐chain amino acid–catabolizing enzymes in intertissue signaling, metabolic remodeling, and energy homeostasis. FASEB J. 33, 8711–8731 (2019). http://www.fasebj.org

show abstract

“…In animals, 3-HIB is secreted from muscle cells, activates endothelial fatty acid transport, stimulates muscle fatty acid uptake in vivo, and promotes muscle lipid accumulation and insulin resistance (34). In human studies, 3-HIB was shown to be related to insulin resistance in individuals with overweight and obesity, and changes in 3-HIB were associated with metabolic improvements with weight loss (35). Finally, leucine supplementation led to abnormal catabolism of BCAA, and the incompletely oxidized lipid species contributed to mitochondrial dysfunction in skeletal muscle in high-fat diet-fed rats (36).…”

Section: Discussionmentioning

confidence: 99%

Daily Branched‐Chain Amino Acid Intake and Risks of Obesity and Insulin Resistance in Children: A Cross‐Sectional Study

Lü

Liu

et al. 2020

Obesity

View full text Add to dashboard Cite

This study aimed to investigate the association of daily branched-chain amino acid (BCAA) intake with the risks of obesity and insulin resistance in children of mothers with gestational diabetes mellitus (GDM). Methods: Daily BCAA intake was calculated by using a validated food frequency questionnaire in 996 children of mothers with GDM. The odds ratios (ORs) (95% CI) of childhood obesity and insulin resistance were obtained using logistic regression models. Results: The multivariable-adjusted ORs for overweight and insulin resistance increased across quartiles of daily BCAA intake (P < 0.05 for trend). Multivariable-adjusted ORs for each 1-SD increase in BCAA intake were 1.37 (1.16-1.62) for overweight and 1.19 (1.02-1.38) for insulin resistance. After additional adjustment of children's daily total energy intake, the OR was still significant for overweight risk but no longer significant for insulin resistance. There were positive associations of daily leucine, isoleucine, and valine intake with the risks for overweight and insulin resistance. Conclusions: Daily BCAA intake was associated with increased risks for overweight and insulin resistance in children of mothers with GDM, but this association was not fully independent of children's daily energy intake. Restriction in dietary BCAA may help prevent childhood obesity and insulin resistance.

show abstract

Branched-chain amino acid catabolism rather than amino acids plasma concentrations is associated with diet-induced changes in insulin resistance in overweight to obese individuals

Cited by 39 publications

References 29 publications

3-Hydroxyisobutyrate, A Strong Marker of Insulin Resistance in Type 2 Diabetes and Obesity That Modulates White and Brown Adipocyte Metabolism

3-Hydroxyisobutyrate, A Strong Marker of Insulin Resistance in Type 2 Diabetes and Obesity That Modulates White and Brown Adipocyte Metabolism

Role of branched‐chain amino acid–catabolizing enzymes in intertissue signaling, metabolic remodeling, and energy homeostasis

Daily Branched‐Chain Amino Acid Intake and Risks of Obesity and Insulin Resistance in Children: A Cross‐Sectional Study

Contact Info

Product

Resources

About