Dietary betaine prevents obesity through gut microbiota-drived microRNA-378a family.

Betaine is a natural compound present in commonly consumed foods and may have a potential role in the regulation of glucose and lipids metabolism. However, the underlying molecular mechanism of its action remains largely unknown. Here, we show that supplementation with betaine contributes to improved high-fat diet (HFD)-induced gut microbiota dysbiosis and increases anti-obesity strains such as Akkermansia muciniphila, Lactobacillus, and Bifidobacterium. In mice lacking gut microbiota, the functional role of betaine in preventing HFD-induced obesity, metabolic syndrome, and inactivation of brown adipose tissues are significantly reduced. Akkermansia muciniphila is an important regulator of betaine in improving microbiome ecology and increasing strains that produce short-chain fatty acids (SCFAs). Increasing two main members of SCFAs including acetate and butyrate can significantly regulate the levels of DNA methylation at host miR-378a promoter, thus preventing the development of obesity and glucose intolerance. However, these beneficial effects are partially abolished by Yin yang (YY1), a common target gene of the miR-378a family. Taken together, our findings demonstrate that betaine can improve obesity and associated MS via the gut microbiota-derived miR-378a/YY1 regulatory axis, and reveal a novel mechanism by which gut microbiota improve host health.

The regulation of skeletal muscle fiber-type composition by betaine is associated with NFATc1/MyoD.

Increasing evidence indicates that muscular dysfunction or alterations in skeletal muscle fiber-type composition not only are involved in muscle metabolism and function but also can limit functional capacity. Therefore, understanding the mechanisms regulating key events during skeletal myogenesis is necessary. Betaine is a naturally occurring component of commonly eaten foods. Here, we showed that 10 mM betaine supplementation in vitro significantly repressed myoblast proliferation and enhanced myoblast differentiation. This effect can be mediated by regulation of miR-29b-3p. Further analysis showed that betaine supplementation in vitro regulated skeletal muscle fiber-type composition through the induction of NFATc1 and the negative regulation of MyoD expression. Furthermore, mice fed with 10 mM betaine in water for 133 days showed no impairment in overall health. Consistently, betaine supplementation increased muscle mass, promoted muscle formation, and modulated the ratio of fiber types in skeletal muscle in vivo. These findings shed light on the diverse biological functions of betaine and indicate that betaine supplementation may lead to new therapies for diseases such as muscular dystrophy or other diseases related to muscle dysfunction. KEY MESSAGES: Betaine supplementation inhibits proliferation and promotes differentiation of C2C12 myoblasts. Betaine supplementation regulates fast to slow muscle fiber-type conversion and is associated with NFATc1/MyoD. Betaine supplementation enhances skeletal myogenesis in vivo. Betaine supplementation does not impair health of mice.

Betaine Supplementation Enhances Lipid Metabolism and Improves Insulin Resistance in Mice Fed a High-Fat Diet.

Obesity is a major driver of metabolic diseases such as nonalcoholic fatty liver disease, certain cancers, and insulin resistance. However, there are no effective drugs to treat obesity. Betaine is a nontoxic, chemically stable and naturally occurring molecule. This study shows that dietary betaine supplementation significantly inhibits the white fat production in a high-fat diet (HFD)-induced obese mice. This might be due to betaine preventing the formation of new white fat (WAT), and guiding the original WAT to burn through stimulated mitochondrial biogenesis and promoting browning of WAT. Furthermore, dietary betaine supplementation decreases intramyocellular lipid accumulation in HFD-induced obese mice. Further analysis shows that betaine supplementation reduced intramyocellular lipid accumulation might be associated with increasing polyunsaturated fatty acids (PUFA), fatty acid oxidation, and the inhibition of fatty acid synthesis in muscle. Notably, by performing insulin-tolerance tests (ITTs) and glucose-tolerance tests (GTTs), dietary betaine supplementation could be observed for improvement of obesity and non-obesity induced insulin resistance. Together, these findings could suggest that inhibiting WAT production, intramyocellular lipid accumulation and inflammation, betaine supplementation limits HFD-induced obesity and improves insulin resistance.