Oral succinate protects the heart in a temperature dependent manner in mice via gut microbiota

Ambient temperature profoundly influences cardiac metabolism and function, but whether it modulates the cardiac effects of an oral metabolite remains largely unexplored. Here, we investigated whether ambient temperature modulates the cardiac effects of oral succinate administration in a mouse model of abdominal aortic coarctation (AAC)-induced cardiac remodeling. Oral succinate attenuated cardiac hypertrophy, fibrosis, and improved survival under cold exposure (16 °C), whereas it exacerbated remodeling at thermoneutrality (30 °C). The protective effect at 16 ℃ was fully preserved in UCP1 deficient mice and after surgical ablation of the interscapular BAT depot, indicating that UCP1 mediated thermogenesis and the interscapular BAT depot are not required for succinate's protection. However, we cannot exclude the possibility that other brown or beige adipose depots may contribute to the observed protection. In contrast, antibiotic mediated perturbation of the gut microbiota abolished succinate's protective effect on the heart. Collectively, these findings demonstrate that succinate exerts temperature dependent and dichotomous effects on cardiac remodeling-protective in the cold but detrimental at thermoneutrality-independent of the interscapular BAT depot and UCP1, but requiring antibiotic sensitive components of the gut microbiota in mice. This study provides evidence for the gut microbiota as a required contributor to the temperature dependent effects of succinate on cardiac remodeling.