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

ABSTRACT: Timed-feeding leads to adipose browning, although the integrative mechanisms for the same remain unclear. Here we show that twice-a-nocturnal (TAN) feeding causes 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 sWAT resulting in increased energy expenditure. Single-cell RNAseq analyses and flow cytometry reveal a role for insulin and leptin surges in ILC2 recruitment and sWAT browning, since depleting leptin or blocking insulin receptor signaling or ILC2 cell recruitment, each dampens TAN feeding-induced sWAT remodeling and energy expenditure. Consistently, recreating insulin and leptin oscillations via once-a-day co-injections is sufficient to favorably remodel innervated sWAT. Indeed, innervation is necessary for sWAT remodeling since denervation of sWAT, but not BAT, blocks TAN-induced sWAT remodeling and resolution of inflammation. In sum, timed feeding reorganizes nutrient-sensitive pathways to remodel sWAT, which drives the metabolic benefits of timed-feeding.

ORGANISM(S): Mus musculus

PROVIDER: GSE263899 | GEO | 2024/04/15

REPOSITORIES: GEO

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Project description:We previously reported that a low versus high glycemic index (GI) diet on a high fat (30% kcal fat) background (LGI and HGI, respectively) significantly retarded adverse health effects in C57BL/6J male mice. The LGI diet enhanced whole body insulin sensitivity and repressed high fat diet-induced body and adipose tissue weight gain, resulting in reduced serum leptin and resistin levels (Faseb J 2009; 23: 1092-1101). How white adipose tissue (WAT) is effected is examined in the present study. We characterized the molecular mechanisms underlying the GI-mediated effects in WAT using whole genome transcriptomics technology. We show that a LGI vs. HGI diet mainly exerts its beneficial effects on substrate metabolism, especially insulin signaling of fatty acid metabolism. In addition, cell adhesion and cytoskeleton remodeling showed reduced expression in line with lower WAT mass, but it might also be due to altered insulin sensitivity. An important transcription factor showing enhanced expression is PPARgamma. Furthermore, serum levels of triglycerides, total cholesterol, HDL- and LDL-cholesterol were significantly reduced by a LGI vs. HGI diet, and muscle insulin sensitivity was significantly increased as analyzed by PKB/Akt phosphorylation. Cumulatively, even though these mice were fed a high fat diet, the low versus high GI induced significantly favorable changes in metabolism in WAT. These effects suggest a partial overlap with pharmacological approaches by thiazolidinediones (TZDs) to treat insulin resistance and statins and plantsterols/stanols for hypercholesterolemia. It is therefore tempting to speculate that such a dietary approach might beneficially support pharmacological treatment of insulin resistance or hypercholesterolemia in humans. We analyzed 19 epididymal whie adipose tissue (epiWAT) samples from a 13 week High fat diet, Low glycemic index dietary group (LGI, n=9) versus a High fat diet, High glycemic index dietary group (HGI, n=10) after 13 weeks of feeding wildtype C57BL/6J male adult mice. Of the 19 arrays, we excluded 2 arrays for downstream analysis based on quality control (total final set contains 8 LGI and 9 HGI samples).

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

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