Tyrosine hydroxylase deletion in Ntsr1 neurons confers resistance to diet-induced weight gain: an energy-balance analysis

A study reveals that a deletion of the tyrosine hydroxylase gene in Ntsr1 neurons provides protection against weight gain induced by a high-fat diet. High-fat diets can disrupt normal circadian feeding patterns and contribute to obesity, but the specific neural mechanisms are not fully understood. Previous research indicated that dopamine production in Ntsr1-expressing neurons is necessary for high-fat diet-induced daytime overeating and obesity development.

Researchers investigated whether resistance to high-fat diet-induced weight gain in Ntsr1Cre;Thflox conditional knockout mice was due to differences in energy expenditure. They measured food intake, indirect calorimetry, activity levels, body temperature, fecal energy, nonesterified fatty acids in feces, and the gut microbiome in both normal and knockout mice.

The knockout mice were resistant to weight gain on a high-fat diet, consuming food readily without significant weight loss on a standard chow diet. However, their feeding patterns were slightly and variably reduced on a high-fat diet compared to a standard chow diet. Unlike the previous study, daytime feeding was not suppressed in the knockout mice, but their energy expenditure, activity levels, body temperature, and gut microbiome composition did not show increased energy expenditure or thermogenesis.

Instead, the knockout mice exhibited reduced energy expenditure and activity, as well as lower body temperature on both diets. In the replication cohort, the high-fat diet resulted in lower fecal output in the knockout mice, although the independent bomb calorimetry cohort showed no significant difference in fecal mass. The fecal energy density and nonesterified fatty acid concentration were unchanged between the two groups.

Preliminary analysis of the gut microbiome suggested a resistant profile in the knockout mice. These findings suggest that the feeding phenotype and obesity resistance are dependent on the diet and experimental conditions, and that increased energy expenditure, activity, thermogenesis, or detectable changes in fecal energy or fat content are not responsible for the observed resistance to high-fat diet-induced weight gain.