A diurnal serum lipid integrates hepatic lipogenesis and peripheral fatty acid use

Abstract

Food intake increases the activity of hepatic de novo lipogenesis, which mediates the conversion of glucose to fats for storage or utilization. In mice, this program follows a circadian rhythm that peaks with nocturnal feeding1,2 and is repressed by Rev-erbα/β and an HDAC3-containing complex3–5 during the day. The transcriptional activators controlling rhythmic lipid synthesis in the dark cycle remain poorly defined. Disturbances in hepatic lipogenesis are also associated with systemic metabolic phenotypes6–8, suggesting that lipogenesis in the liver communicates with peripheral tissues to control energy substrate homeostasis. Here we identify a PPARδ-dependent de novo lipogenic pathway in the liver that modulates fat utilization by muscle via a circulating lipid. The nuclear receptor PPARδ controls diurnal expression of lipogenic genes in the dark/feeding cycle. Liver-specific PPARδ activation increases, while hepatocyte-Ppard deletion reduces, muscle fatty acid (FA) uptake. Unbiased metabolite profiling identifies PC(18:0/18:1), or 1-stearoyl-2-oleoyl-sn-glycero-3-phosphocholine (SOPC), as a serum lipid regulated by diurnal hepatic PPARδ activity. PC(18:0/18:1) reduces postprandial lipid levels and increases FA utilization through muscle PPARα. High fat feeding diminishes rhythmic production of PC(18:0/18:1), whereas PC(18:0/18:1) administration in db/db mice improves metabolic homeostasis. These findings reveal an integrated regulatory circuit coupling lipid synthesis in the liver to energy utilization in muscle by coordinating the activity of two closely related nuclear receptors. These data implicate alterations in diurnal hepatic PPARδ-PC(18:0/18:1) signaling in metabolic disorders including obesity.

Shifting the feeding of mice to the rest phase creates metabolic alterations, which, on their own, shift the peripheral circadian clocks by 12 hours

“…As this delay disappeared in ADX mice, it was ascribed to the RF extra-corticosterone production (18). Interestingly, PPARα activation in muscle and heart is dependent on the expression of PPARβ in liver (19), which reaches its zenith at ZT20-ZT4 (Fig. 5E).…”

Coupling of lipolysis and de novo lipogenesis in brown, beige, and white adipose tissues during chronic β3-adrenergic receptor activation

“…DNL produces lipid species that are biologically active and are functionally distinct from dietary lipids ( 47,48 ), as is the case with the production of a FASN-dependent PPAR ␥ ligand in adipose tissue ( 49 ). In this regard, PPAR ␦ activation in liver generates ligands that activate skeletal muscle PPAR ␣ , thereby matching hepatic lipogenesis with muscle lipid oxidation ( 50 ). Whether such cross talk occurs among or within fat depots requires additional exploration.…”

Hepatic oleate regulates adipose tissue lipogenesis and fatty acid oxidation

“…For example, Liu et al ( 38 ) recently demonstrated that endogenous, but not exogenous, oleate and palmitoleate inhibit the activity of fatty acid amide hydrolase, an enzyme that degrades endocannabinoids, and explains the mechanism through which endocannabinoids decrease insulin sensitivity. Activation of Wnt proteins requires them to fi rst become acylated with palmitoleate ( 39 ), while oleate is a required component of specifi c GP species that activate PPAR ␣ in the liver ( 40 ) and muscle ( 41 ). Perhaps enzymes in the fatty acid oxidation or synthesis and lipid storage homeostasis are both sensitive to hepatic oleate production, where one of the major products of SCD activity can infl uence the balance of storage and utilization in adipose tissue.…”