Nadia Romp1, Moyan Liu1, Youling Hao1, , Stefan Havik1, Fabiola Fanini1, Jakshana Ananthasabesan1, Max Nieuwdorp2,3, Hilde Herrema1, Elena Rampanelli1,4
1 Amsterdam UMC location Academic Medical Center, Department of Experimental Vascular Medicine, Amsterdam, The Netherlands.
2 Amsterdam UMC location Academic Medical Center, Department of Vascular Medicine, Amsterdam, The Netherlands.
3 Diabeter Centrum Amsterdam, Amsterdam, The Netherlands
4 Amsterdam Institute for Infection and Immunity, Amsterdam, The Netherlands.
Obesity and associated type 2 diabetes (T2D) are highly prevalent metabolic disorders and major contributors to cardiometabolic complications. Alterations in gut microbiota composition and function have been implicated in diabetes progression through metabolite-mediated regulation of host metabolism.
We recently identified the microbiota-derived metabolite 6-bromotryptophan (6-BT) as a potential regulator of metabolic health. In both a population-based cohort and a cohort of patients with severe obesity, lower plasma concentrations of 6-BT were associated with a higher prevalence of T2D, increased HbA1c levels, and an adverse lipid profile, suggesting a protective role for 6-BT in glucose and lipid homeostasis.
Prompted by these clinical observations, we investigated the effects of 6-BT in two complementary mouse models of obesity and T2D: genetically diabetic db/db mice and diet-induced obese (DIO) mice, representing severe and more physiologically relevant models of obesity and T2D, respectively. Mice received 6-BT at a dose of 20 mg/kg by either intraperitoneal injection or oral gavage. In db/db mice, 6-BT administration markedly reduced adiposity, as demonstrated by decreased white adipose tissue (WAT) mass, reduced adipocyte hypertrophy, and diminished macrophage infiltration into WAT. In addition, steatosis and inflammation were significantly reduced in both the liver and kidneys. Similarly, in DIO mice, 6-BT supplementation reduced liver weight and kidney fibrosis while improving glucose metabolism, as evidenced by a lower glucose area under the curve during glucose tolerance testing.
Moreover, 6-BT exposure upregulated the expression of genes involved in mitochondrial beta-oxidation, reduced intracellular lipid accumulation, and promoted mitochondrial oxidative metabolism in adipocytes. Mechanistic in vitro studies revealed that 6-BT is transported into cells via the amino acid transporters SLC7A5 and SLC16A10, where it activates the SIRT1-AMPK pathway, consequently enhancing mitochondrial oxidative metabolism.
Collectively, our findings highlight the potential of 6-BT as a natural therapeutic agent to counteract adiposity/T2D and alleviate chronic inflammation. Further studies are warranted to investigate its efficacy in other metabolic and inflammatory diseases.