Global analysis of plasma lipids identifies liver-derived acyl-carnitines as a fuel source for brown fat thermogenesis

Abstract

SummaryCold induced thermogenesis is an energy demanding process that protects endotherms against a reduction in ambient temperature. Using non-targeted LC-MS based lipidomics, we identified plasma acylcarnitines as the most significantly changed lipid class in response to the cold. Here we show that acylcarnitines provide fuel for brown fat thermogenesis. In response to the cold, FFAs released from adipocytes activate the nuclear receptor HNF4α to stimulate the expression of genes involved in acylcarnitine metabolism in the liver. Conditional deletion of HNF4α in hepatocytes blocks the cold-induced changes in hepatic gene expression, lowering circulating long chain acylcarnitine (LCAC) levels, and impairing their ability to adapt to the cold. Finally, a bolus of L-carnitine or palmitoylcarnitine rescues the cold sensitivity seen with aging. Our data highlights an elegant mechanism whereby white adipose tissue provides FFAs for hepatic carnitilation to generate plasma LCAC as a fuel source for BAT thermogenesis.HighlightsBlood acylcarnitine levels increase in response to the cold.FFA mobilization in response to the cold activates hepatic HNF4α and stimulates genes involved in acylcarnitine metabolism.Brown adipocytes metabolize palmitoylcarnitine.Carnitine administration improves thermogenic response in aged mice.ETOCSimcox et al identified acylcarnitines as a novel source of energy for thermogenesis. In response to the cold, the liver activates a transcriptional program through the transcription factor HNF4α, leading to increased acylcarnitine levels. They also find that aging mice have reduced acylcarnitine levels and an impaired thermogenic response in the cold. Increasing acylcarnitine levels in old mice increases their ability to adapt to the cold. Their studies discover a physiological role for acylcarnitines in thermogenesis.Graphical AbstractCold exposure stimulates the sympathetic nervous system to release noradrenaline (NA). Activation of β3-adrenergic receptors stimulates FFA release and activation of the transcription factor HNF4α in the liver. This leads to increased gene expression of enzymes involved in acylcarnitine metabolism. The acylcarnitines are released in the blood to provide fuel for brown fat thermogenesis. These studies highlight the role of the liver in the thermogenic response.