The intestinal microbiome produces short-chain fatty acids (SCFAs) from dietary fiber and has specific effects on other organs. During endurance exercise, fatty acids, glucose, and amino acids are major energy substrates. However, little is known about the role of SCFAs during exercise. To investigate this, mice were administered either multiple antibiotics or a low microbiome-accessible carbohydrate (LMC) diet, before endurance testing on a treadmill. Two-week antibiotic treatment significantly reduced endurance capacity versus the untreated group. In the cecum acetate, propionate, and butyrate became almost undetectable in the antibiotic-treated group, plasma SCFA concentrations were lower, and the microbiome was disrupted. Similarly, 6-wk LMC treatment significantly reduced exercise capacity, and fecal and plasma SCFA concentrations. Continuous acetate but not saline infusion in antibiotic-treated mice restored their exercise capacity ( P < 0.05), suggesting that plasma acetate may be an important energy substrate during endurance exercise. In addition, running time was significantly improved in LMC-fed mice by fecal microbiome transplantation from others fed a high microbiome-accessible carbohydrate diet and administered a single portion of fermentable fiber ( P < 0.05). In conclusion, the microbiome can contribute to endurance exercise by producing SCFAs. Our findings provide new insight into the effects of the microbiome on systemic metabolism.

Mitochondria are critical in heat generation in brown and beige adipocytes. Mitochondrial number and function are regulated in response to external stimuli, such as cold exposure and β3 adrenergic receptor agonist. However, the molecular mechanisms regulating mitochondrial biogenesis during browning, especially by microRNAs, remain unknown. We investigated the role of miR-494-3p in mitochondrial biogenesis during adipogenesis and browning. Intermittent mild cold exposure of mice induced PPARγ coactivator1-α (PGC1-α) and mitochondrial TFAM, PDH, and ANT1/2 expression along with uncoupling protein-1 (Ucp1) in inguinal white adipose tissue (iWAT). miR-494-3p levels were significantly downregulated in iWAT upon cold exposure (p < 0.05). miR-494-3p overexpression substantially reduced PGC1-α expression and its downstream targets TFAM, PDH and MTCO1 in 3T3-L1 white and beige adipocytes (p < 0.05). miR-494-3p inhibition in 3T3-L1 white adipocytes resulted in increased PDH (p < 0.05). PGC1-α, TFAM and Ucp1 mRNA levels were robustly downregulated by miR-494-3p overexpression in 3T3-L1 beige adipocytes, along with strongly decreased oxygen consumption rate. PGC1-α and Ucp1 proteins were downregulated by miR-494-3p in primary beige cells (p < 0.05). Luciferase assays confirmed PGC1-α as a direct gene target of miR-494-3p. Our findings demonstrate that decreased miR-494-3p expression during browning regulates mitochondrial biogenesis and thermogenesis through PGC1-α.

Amla is one of the most important plants in Indian traditional medicine and has been shown to improve various age-related disorders while decreasing oxidative stress. Mitochondrial dysfunction is a proposed cause of aging through elevated oxidative stress. In this study, we investigated the effects of Amla on mitochondrial function in C2C12 myotubes, a murine skeletal muscle cell model with abundant mitochondria. Based on cell flux analysis, treatment with an extract of Amla fruit enhanced mitochondrial spare respiratory capacity, which enables cells to overcome various stresses. To further explore the mechanisms underlying these effects on mitochondrial function, we analyzed mitochondrial biogenesis and antioxidant systems, both proposed regulators of mitochondrial spare respiratory capacity. We found that Amla treatment stimulated both systems accompanied by AMPK and Nrf2 activation. Furthermore, we found that Amla treatment exhibited cytoprotective effects and lowered reactive oxygen species (ROS) levels in cells subjected to t-BHP-induced oxidative stress. These effects were accompanied by increased oxygen consumption, suggesting that Amla protected cells against oxidative stress by using enhanced spare respiratory capacity to produce more energy. Thus we identified protective effects of Amla, involving activation of mitochondrial function, which potentially explain its various effects on age-related disorders.

Adipose tissues considerably influence metabolic homeostasis, and both white (WAT) and brown (BAT) adipose tissue play significant roles in lipid and glucose metabolism. -linked-acetylglucosamine (-GlcNAc) modification is characterized by the addition of -acetylglucosamine to various proteins by-GlcNAc transferase (Ogt), subsequently modulating various cellular processes. However, little is known about the role of -GlcNAc modification in adipose tissues. Here, we report the critical role of-GlcNAc modification in cold-induced thermogenesis. Deletion of in WAT and BAT using adiponectin promoter-driven Cre recombinase resulted in severe cold intolerance with decreased uncoupling protein 1 (Ucp1) expression. Furthermore, deletion led to decreased mitochondrial protein expression in conjunction with decreased peroxisome proliferator-activated receptor γ coactivator 1-α protein expression. This phenotype was further confirmed by deletion of in BAT using Ucp1 promoter-driven Cre recombinase, suggesting that-GlcNAc modification in BAT is responsible for cold-induced thermogenesis. Hypothermia was significant under fasting conditions. This effect was mitigated after normal diet consumption but not after consumption of a fatty acid-rich ketogenic diet lacking carbohydrates, suggesting impaired diet-induced thermogenesis, particularly by fat. In conclusion, -GlcNAc modification is essential for cold-induced thermogenesis and mitochondrial biogenesis in BAT. Glucose flux into BAT may be a signal to maintain BAT physiological responses.

No abstract