SUMMARY Hepatic lipogenesis is nutritionally regulated, i.e., downregulated during fasting and upregulated during the postprandial state, as an adaptation to the nutritional environment. While alterations in the expression level of the transcription factor SREBP-1c are known to be critical for nutritionally-regulated lipogenesis, upstream mechanisms governing Srebf1 gene expression remain unclear. Here we show that the fasting-induced transcription factor KLF15, a key regulator of gluconeogenesis, forms a complex with LXR/RXR, specifically on the Srebf1 promoter. This complex recruits the corepressor RIP140 instead of the coactivator SRC1, resulting in reduced Srebf1 and thus downstream lipogenic enzyme expression during the early and euglycemic period of fasting prior to hypoglycemia and PKA activation. Through this mechanism, KLF15 overexpression specifically ameliorates hypertriglyceridemia without affecting LXR-mediated cholesterol metabolism. These findings reveal a key molecular link between glucose and lipid metabolism with therapeutic implications for the treatment of hyperlipidemia.

During fasting, animals maintain their energy balance by shifting their energy source from carbohydrates to triglycerides. However, the trigger for this switch has not yet been entirely elucidated. Here we show that a selective hepatic vagotomy slows the speed of fat consumption by attenuating sympathetic nerve-mediated lipolysis in adipose tissue. Hepatic glycogen pre-loading by the adenoviral overexpression of glycogen synthase or the transcription factor TFE3 abolished this liver–brain–adipose axis activation. Moreover, the blockade of glycolysis through the knockdown of the glycogen phosphorylase gene and the resulting elevation in the glycogen content abolished the lipolytic signal from the liver, indicating that glycogen is the key to triggering this neurocircuitry. These results demonstrate that liver glycogen shortage activates a liver–brain–adipose neural axis that has an important role in switching the fuel source from glycogen to triglycerides under prolonged fasting conditions.

In patients with SAP, administration of a large fluid volume within the first 24 hours is associated with decreased mortality.

Highlights d Feeding elevates serum LPS and insulin, which induce IL-10 in macrophages in vitro d Insulin and LPS/insulin-treated macrophage medium suppress gluconeogenic genes d Myeloid IL-10-deficient mouse models show dysregulated postprandial glycemia d IL-10 expression in obese mice restores postprandial gluconeogenic gene suppression