Circadian lipid synthesis in brown fat maintains murine body temperature during chronic cold

Abstract

Ambient temperature influences the molecular clock and lipid metabolism, but the impact of chronic cold exposure on circadian lipid metabolism in thermogenic brown adipose tissue (BAT) has not been studied. Here we show that during chronic cold exposure (1 wk at 4 °C), genes controlling de novo lipogenesis (DNL) includingSrebp1, the master transcriptional regulator of DNL, acquired high-amplitude circadian rhythms in thermogenic BAT. These conditions activated mechanistic target of rapamycin 1 (mTORC1), an inducer ofSrebp1expression, and engaged circadian transcriptional repressors REV-ERBα and β as rhythmic regulators ofSrebp1in BAT. SREBP was required in BAT for the thermogenic response to norepinephrine, and depletion of SREBP prevented maintenance of body temperature both during circadian cycles as well as during fasting of chronically cold mice. By contrast, deletion of REV-ERBα and β in BAT allowed mice to maintain their body temperature in chronic cold. Thus, the environmental challenge of prolonged noncircadian exposure to cold temperature induces circadian induction of SREBP1 that drives fuel synthesis in BAT and is necessary to maintain circadian body temperature during chronic cold exposure. The requirement for BAT fatty acid synthesis has broad implications for adaptation to cold.

Multi-omics Analysis of the Intermittent Fasting Response in Mice Identifies an Unexpected Role for HNF4α

“…One cause for the lower liver lipids in fasted EODF animals could be the increased energy expenditure from WAT browning seen previously (Li et al, 2017). However, given our liver EODF-induced protein changes of a increased DNL enzymes and fatty acid oxidation enzymes regardless of harvest state, these animals may have coupled the pathway of DNL with fatty acid oxidation to generate a futile energy-consuming cycle (Solinas et al 2015), similar to that of brown adipose tissue (Adlanmerini et al, 2019). This could also contribute to the elevated body temperature of EODF mice seen previously (Li et al, 2017), as the liver can participate in non-shivering thermogenesis (Stoner, 1973).…”

“…Likewise, liver-specific FASN mutants display detrimental phenotypes compared to wild-type animals, including greatly increased steatosis after fasting (Chakravarthy et al, 2005). Furthermore, two recent studies have shown that DNL is needed for fasting-induced fatty acid oxidation in brown adipose tissue (Adlanmerini et al, 2019;Sanchez-Gurmaches et al, 2018). These studies show that DNL may be directly coupled to fatty acid oxidation under certain circumstances to generate a futile cycle that wastes energy as heat.…”

Hypothalamic REV-ERB nuclear receptors control diurnal food intake and leptin sensitivity in diet-induced obese mice

“…We first determined the diurnal expression of REV-ERBa in non-SCN hypothalamic nuclei of mice with epitopetagged endogenous REV-ERBa (HA-REV-ERBa mice, previously described 23 ) to specifically visualize the protein by immunofluorescence. Peak expression was observed between zeitgeber time (ZT) 1-7 ( Figure 1A), and thus studies of REV-ERBs function in hypothalamus were conducted at ZT 1-4.…”

“…To delineate hypothalamic-specific functions of REV-ERBs, mice homozygous for floxed alleles of REV-ERBa and REV-ERBb 23,24 were crossed to Nkx2.1-Cre mice, which express Cre in the ventromedial tuberal hypothalamic nuclei but, importantly, not in the SCN 25 . This Cre driver is also expressed in the lung and thyroid gland but not in any other peripheral metabolic organs 25,26 .…”

“…Reverba flox/flox -Reverbb flox/flox mice 24 were bred to C57BL/6J-Tg(Nkx2.1-Cre)2Sand/J mice maintained on a C57BL/6J background (Jackson Labs Technologies, Inc., Stock 008661). HA-REV-ERBa mice were generated and maintained on C57BL/6J genetic background 23 Total RNA was isolated from snap-frozen brown adipose tissue, white adipose tissue and liver, which were mechanically homogenized in TRIzol (Life Technologies) using a TissueLyser (Qiagen) for 2min. Following RNA extraction with chloroform, mRNA was further purified with RNeasy Mini spin columns (Qiagen) and on-column DNase-digestion (Qiagen).…”