Konjac glucomannan (KGM) is used for appetite management. However, KGM's regulation of appetite through hypothalamic neurons and gut microbiota, particularly in nonobese populations, is required to be investigated. This study investigated the differential effects of KGM on appetite and energy metabolism in obese and nonobese mice. In obese mice, KGM inhibited food intake, hypothalamic inflammation, and increased energy expenditure. Conversely, in nonobese mice, KGM maintained food intake and energy expenditure but increased hypothalamic inflammation. KGM downregulated hypothalamic Agrp, Npy, and Orx expression and upregulated Cart in obese mice, while it had no effect on orexigenic genes and downregulated Cart in nonobese mice. Additionally, KGM reshaped gut microbiota and increased Short-chain fatty acids (SCFAs) formation of obese mice, where Alistipes, Bifidobacterium, and Lactobacillus, as well as SCFAs, correlated with suppressed appetite. In nonobese mice, KGM has no significant effect on SCFAs but microbes such as Blautia, Alistipes, and Flavonifractor levels were negatively correlated with hypothalamic inflammation. KGM maintains appetite and was linked to liver-derived phosphatidylcholine, countering increased hypothalamic inflammation. The differential regulation of appetite by KGM between obese and nonobese mice is associated with hypothalamic inflammatory, neuronal, and KGM-induced personalized reshaping of gut microbiota. KGM may regulate energy intake and expenditure through the microbiota-gut-brain axis.
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