The effects of low-fat dairy products on insulin resistance (IR), hepatic steatosis, and gut microbiota composition in high-fat diet (HFD)-fed obese mice were examined. C57BL/6 male mice (n = 16/group) were fed a high-fat diet (HFD, 45% fat) or HFD supplemented with either fat-free milk (MILK), fat-free yogurt (YOG), or reduced-fat (19% milk fat) cheddar cheese (CHE) at 10% of the total energy intake for 8 weeks. Body weight, fat mass, liver lipids, and metabolic enzymes were evaluated. Compared with HFD, MILK reduced homeostatic assessment of insulin resistance along with increased hepatic insulin signaling and decreased hepatic gluconeogenic enzymes. YOG and MILK decreased hepatic triacylglycerol content and lipid droplet size, while CHE had no effect. In the liver, MILK and YOG downregulated de novo lipogenesis enzymes. In MILK, fat oxidation capacity was elevated. Compared with HFD, liver lipidomic analysis in MILK and YOG revealed unique profiles of decreased proinflammatory lipid species, including ceramides. Dairy feeding elicited an increase in beneficial bacteria, such as Streptococcus in YOG and Anaero-tignum in MILK, as shown by 16S rRNA sequencing of gut microbiota. In conclusion, the ability of milk and yogurt to reduce hepatic steatosis in HFD mice may be explained, at least in part, by the regulation of the gut microbiome and liver lipidome.

Aim: We hypothesized that milk, yogurt, and cheese have differential impacts on energy expenditure (EE) and obesity in mice fed a high-fat diet (HFD). Methods: C57BL/6 mice (n = 16 per group) were fed a HFD or a HFD supplemented with fat-free milk (MILK), fat-free plain yogurt (YOG), or reduced-fat cheddar cheese (CHE; 19 kcal% fat), each provided at 10% of the daily energy intake, for 8 weeks. EE was quantified using a metabolic chamber. Metabolic pathways related to BAT mitochondrial function and uncoupling protein 1 (UCP1) abundance were assessed. Serum lipidomic profiles were analyzed to identify potential mediators of the observed effects. Results: MILK supplementation lowered weight gain and fat accumulation and enhanced EE and BAT thermogenesis, perhaps via the SIRT1-AMPK-PGC1α axis in BAT. This led to elevated UCP1 abundance and enhanced the abundance of hormone-sensitive lipase (HSL). MILK also altered serum lipid species, indicating enhanced energy use, and promoted BAT thermogenesis and mitochondrial function pathways. YOG exhibited a similar pattern but a lower magnitude of effects than MILK on reducing weight gain and fat mass, increasing EE, and BAT thermogenic proteins, including AMPK-PGC1α-UCP1. Both MILK and YOG showed a relative increase in serum PC 15:0_15:0 and LPC 15:0. In contrast, CHE reduced weight gain and increased EE without impacting BAT thermogenesis proteins or serum lipid species. Conclusion: Our study showed that MILK, YOG, and CHE reduced weight gain in mice on a HFD by increasing EE. MILK and YOG also up-regulated BAT thermogenesis, while both additionally altered lipids involved in fat metabolism and inflammation. CHE did not affect BAT thermogenesis and lipid species compared to HFD.