This study investigates the impact of a high-fat diet (HFD) on spontaneous physical activity (SPA) and non-exercise activity thermogenesis (NEAT), and the potential therapeutic effect of orexin neuron activation on these parameters. The researchers hypothesized that HFD consumption would decrease SPA and NEAT, leading to increased inactivity after meals. They used continuous metabolic phenotyping to measure food intake, SPA, and NEAT in mice over a 10-day period. Mice were divided into two cohorts: one cohort switched from a standard chow diet to an HFD, and the other cohort was given access to either chow or HFD. For the HFD group, orexin neuron activation was induced using DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) with clozapine N-oxide (CNO). Results showed that mice on HFD spent less time eating and more time inactive compared to those on chow. HFD also increased the likelihood of long bouts of inactivity after meals. NEAT was significantly reduced in HFD-fed mice, but activation of orexin neurons with CNO restored NEAT to control levels. The study suggests that HFD consumption reduces SPA and NEAT, leading to increased inactivity and decreased energy expenditure. Orexin neuron activation has the potential to counteract these negative effects by increasing NEAT and SPA, thereby improving energy expenditure.This study investigates the impact of a high-fat diet (HFD) on spontaneous physical activity (SPA) and non-exercise activity thermogenesis (NEAT), and the potential therapeutic effect of orexin neuron activation on these parameters. The researchers hypothesized that HFD consumption would decrease SPA and NEAT, leading to increased inactivity after meals. They used continuous metabolic phenotyping to measure food intake, SPA, and NEAT in mice over a 10-day period. Mice were divided into two cohorts: one cohort switched from a standard chow diet to an HFD, and the other cohort was given access to either chow or HFD. For the HFD group, orexin neuron activation was induced using DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) with clozapine N-oxide (CNO). Results showed that mice on HFD spent less time eating and more time inactive compared to those on chow. HFD also increased the likelihood of long bouts of inactivity after meals. NEAT was significantly reduced in HFD-fed mice, but activation of orexin neurons with CNO restored NEAT to control levels. The study suggests that HFD consumption reduces SPA and NEAT, leading to increased inactivity and decreased energy expenditure. Orexin neuron activation has the potential to counteract these negative effects by increasing NEAT and SPA, thereby improving energy expenditure.