Trefoil factor family member 2 ( Tff2 ) KO mice are protected from high‐fat diet‐induced obesity

Trefoil factor family member 2 (Tff2) is a small gut peptide, mainly known for its protective and healing functions. As previously demonstrated, high‐fat (HF) feeding can rapidly and specifically modulate Tff2 transcription in key tissues of mice, including the duodenum and mesenteric adipose tissue, therefore suggesting a novel role for this gene in energy balance. Design and Methods To explore whether and how Tff2 can influence feeding behavior and energy metabolism, Tff2 knock‐out (KO) mice were challenged with HF diet for 12 weeks, hence food and energy intakes, body composition, as well as energy excretion and serum lipid and hormonal levels were analyzed. Finally, energy efficiency was estimated. Results Tff2 KO mice showed a greater appetite and higher energy intake compared to wild‐type (WT). Consistently, they presented lower levels of serum leptin, and increased transcription of agouti‐related protein (Agrp) in the hypothalamus. Though energy and triglyceride fecal excretion were augmented in Tff2 KO mice, digestible energy intake was superior. However, KO mice were finally protected from HF diet‐induced obesity, and accumulated less weight and fat depots than WT animals, while keeping a normal lean mass. Energy efficiency was lower in HF‐KO mice, while energy expenditure and locomotor activity were globally increased. Conclusions The present work demonstrates previously unsuspected roles for Tff2 and suggests it to be a mastermind in the control of energy balance and a promising therapeutic target for obesity.