Insulin and leptin oscillations license food-entrained browning and metabolic flexibility

Timed feeding drives adipose browning, although the integrative mechanisms for the same remain unclear. Here, we show that twice-a-night (TAN) feeding generates biphasic oscillations of circulating insulin and leptin, representing their entrainment by timed feeding. Insulin and leptin surges lead to marked cellular, functional, and metabolic remodeling of subcutaneous white adipose tissue (sWAT), resulting in increased energy expenditure. Single-cell RNA-sequencing (scRNA-seq) analyses and flow cytometry demonstrate a role for insulin and leptin surges in innate lymphoid type 2 (ILC2) cell recruitment and sWAT browning, since sWAT depot denervation or loss of leptin or insulin receptor signaling or ILC2 recruitment each dampens TAN feeding-induced sWAT remodeling and energy expenditure. Consistently, recreating insulin and leptin oscillations via once-a-day timed co-injections is sufficient to favorably remodel innervated sWAT. Innervation is necessary for sWAT remodeling, since denervation of sWAT, but not brown adipose tissue (BAT), blocks TAN-induced sWAT remodeling and resolution of inflammation. In sum, reorganization of nutrient-sensitive pathways remodels sWAT and drives the metabolic benefits of timed feeding. [Display omitted] •Two meals per period entrains insulin and leptin oscillations•Insulin and leptin oscillations drive the cellular, immune, and metabolic remodeling of sWAT•sWAT remodeling leads to metabolic flexibility and inflammation resolution in eWAT•Recreating insulin and leptin oscillations pharmacologically recapitulates sWAT remodeling Mattar et al. show that two meals per period entrains insulin and leptin oscillations to drive subcutaneous fat browning and metabolic flexibility. Targeting insulin or leptin signaling or ILC2 cell recruitment or tissue denervation each blocks subcutaneous fat browning in food-entrained mice, while reconstituting endocrine oscillations facilitates adipose browning.