Prolonged fasting drives a program of metabolic inflammation in human adipose tissue

Abstract

Objective The human adaptive fasting response enables survival during periods of caloric deprivation. A crucial component of the fasting response is the shift from glucose metabolism to utilization of lipids, underscoring the importance of adipose tissue as the central lipid-storing organ. The objective of this study was to investigate the response of adipose tissue to a prolonged fast in humans. Methods We performed RNA sequencing of subcutaneous adipose tissue samples longitudinally collected during a 10-day, 0-calorie fast in humans. We further investigated observed transcriptional signatures utilizing cultured human monocytes and Thp1 cells. We examined the cellularity of adipose tissue biopsies with transmission electron microscopy and tested for associated changes in relevant inflammatory mediators in the systemic circulation by ELISA assays of longitudinally collected blood samples. Results Coincident with the expected shift away from glucose utilization and lipid storage, we demonstrated downregulation of pathways related to glycolysis, oxidative phosphorylation, and lipogenesis. The canonical lipolysis pathway was also downregulated, whereas fasting drove alternative lysosomal paths to lipid digestion. Unexpectedly, the dominant induced pathways were associated with immunity and inflammation, although this only became evident at the 10-day time point. Among the most augmented transcripts were those associated with macrophage identity and function, such as members of the erythroblast transformation-specific (ETS) transcription factor family. Key components of the macrophage transcriptional signal in fasting adipose tissue were recapitulated with induced expression of two of the ETS transcription factors via cultured macrophages, SPIC and SPI1 . The inflammatory signal was further reflected by an increase in systemic inflammatory mediators. Conclusions Collectively, this study demonstrates an unexpected role of metabolic inflammation in the human adaptive fasting response.

The dynamics of human bone marrow adipose tissue in response to feeding and fasting

“…CRP, which increased in response to high-calorie feeding, also increased in response to fasting (median increase: 100% [38.3%, 277.0%], P = 0.0003), and GDF15, another inflammatory marker, also increased in response to fasting ( P = 0.0005; Table 2 ). These findings are consistent with the increased inflammatory response observed in prolonged human fasting ( 16 ). Changes in adipokines, bone turnover markers, or inflammatory markers did not predict changes in BMAT during the fasting visit ( Supplemental Table 8 ).…”

Transcriptomic Effects of Healthspan-Promoting Dietary Interventions: Current Evidence and Future Directions

“…In humans, a prolonged 10-day fast results in transcriptomic signatures of increased lipolysis/lipid metabolism and reduced activation of pathways related to glycolysis and oxidative phosphorylation. Interestingly, this prolonged fasting period also contributes to the upregulation of inflammatory pathways and macrophage activation in subcutaneous fat tissue ( 42 ), reflecting a potential hormesis response and downstream protective mechanisms. Another study showed that short-term fasting is associated with enrichment of transcriptomic pathways involved in fatty acid oxidation, cell cycling and apoptosis, and a decrease in the expression of pro-inflammatory genes in peripheral blood mononuclear cells ( 16 ).…”

The Effects of Prolonged Water-Only Fasting and Refeeding on Markers of Cardiometabolic Risk

“…Surprisingly, the median HOMA-IR, which was 1.4 at baseline and trending downward after fasting (1.1), had more than doubled after refeeding (3.1), suggesting that fasting may increase insulin resistance upon refeeding, at least in this overweight/obese non-diabetic population. Indeed, prolonged fasting may result in temporary physiological changes, such as downregulation of insulin receptor expression [ 45 ], elevated VLDL and TG levels [ 16 , 46 ], and metabolic inflammation in adipose tissue [ 47 ], which could temporarily affect insulin sensitivity during refeeding. We speculate that the observed insulin resistance is a temporary, rebound phenomenon caused by a reversal of the metabolic switch from ketosis back to glycolysis upon refeeding.…”