A Medium Chain Fatty Acid, 6-hydroxyhexanoic acid (6-HHA), Protects Against Obesity and Insulin Resistance

Obesity, a worldwide health problem, increases the risk for developing metabolic diseases such as insulin resistance and diabetes. It is well recognized that obesity-associated chronic inflammation plays a key role in the pathogenesis of systemic metabolic dysfunction. Previously, we revealed an anti-inflammatory role for spent culture supernatants isolated from the oral commensal bacterial species Streptococcus gordonii (Sg-SCS). Here, we identified that 6-hydroxyhexanoic acid (6-HHA), a medium chain fatty acid (MCFA), is the one of the key components of Sg-SCS. We found that treatment of 6-HHA in mice fed a high-fat diet (HFD) significantly reduced HFD-mediated weight gain which was largely attributed to a decrease in fat mass. Systemically, 6-HHA improves obesity-associated glucose intolerance and insulin resistance. Furthermore, administration of 6-HHA suppressed obesity-associated systemic inflammation and dyslipidemia. At the cellular level, treatment of 6-HHA ameliorated aberrant inflammatory and metabolic transcriptomic signatures in white adipose tissue of mice with diet-induced obesity (HFD). Mechanistically, we found that 6-HHA suppressed adipocyte-proinflammatory cytokine production and lipolysis, the latter through Gi-mediated signaling. This work provides direct evidence for the anti-obesity effects of a novel MCFA, which could be a new therapeutic treatment for combating obesity. KEY POINTSO_LIHydroxyhexanoic medium chain fatty acids (MCFAs) are dietary and bacterial-derived energy sources, however, the outcomes of using MCFAs in treating metabolic disorders are diverse and complex. C_LIO_LIThe MCFA 6-hydroxyhexanoic acid (6-HHA) is a metabolite secreted by the oral bacterial commensal species Streptococcus gordonii; here we investigated its role in modulating high-fat diet (HFD)-induced metabolic dysfunction. C_LIO_LIIn a murine model of obesity, we found 6-HHA-mediated improvement of diet-mediated adiposity, insulin resistance and inflammation were in part due to actions on white adipose tissue (WAT). C_LIO_LI6-HHA suppressed proinflammatory cytokine production and lipolysis through Gi-mediated signaling in differentiated white adipocytes. C_LI