Reversal of diet-induced obesity by central insulin sensitizer FSTL1

Follistatin-like 1 (FSTL1) is a signaling molecule that modulates energy metabolism in peripheral tissues and is also expressed in the brain. However, whether hypothalamic FSTL1 regulates carbohydrate/lipid metabolism and energy balance remains unknown. Here, we show that FSTL1 is enriched in the hypothalamus, especially the arcuate nucleus (ARC). FSTL1 expression is decreased in diet-induced obese (DIO) and db/db mice. Agouti-related peptide (AgRP) neuron-specific Fstl1 deletion increased food intake, decreased energy expenditure, and impaired insulin sensitivity in DIO mice. Conversely, Fstl1 overexpression in AgRP neurons resulted in the opposite phenotypes. Insulin signaling was required for the anti-obesity effect of hypothalamic FSTL1. Intranasal FSTL1 delivery promoted weight loss and improved insulin sensitivity in DIO mice. Mechanistically, FSTL1 interacts with Akt, an intracellular mediator of insulin signaling, to inhibit forkhead box protein O1 (FoxO1) nuclear translocation. Our findings identify hypothalamic FSTL1 as a key mediator counteracting DIO and provide a potential pharmacological strategy for obesity-related metabolic disorders.