Apolipoprotein E deficiency activates thermogenesis of white adipose tissues in mice through enhancing β‐hydroxybutyrate production from precursor cells

Abstract

White adipose tissue (WAT) has the capacity to undergo a white-to-beige phenotypic switch, known as browning, in response to stimuli such as cold. However, the mechanism underlying beige adipocyte formation is largely unknown. Apolipoprotein E (ApoE) is highly induced in WAT and has been implicated in lipid metabolism. Here, we show that ApoE deficiency in mice increased oxygen consumption and thermogenesis and enhanced adipose browning pattern in inguinal WAT (iWAT), with associated characteristics such as increased Ucp1 and Pparγ expression. At the cellular level, ApoE deficient beige adipocytes had increased glucose uptake and higher mitochondrial respiration than wild-type cells. Mechanistically, we showed that ApoE deficient iWAT and primary adipose precursor cells activated the thermogenic genes program by stimulating the production of ketone body β-hydroxybutyrate (βHB), a novel adipose browning promoting factor. This was accompanied by increased expression of genes involved in ketogenesis and could be compromised by the treatment for ketogenesis inhibitors. Consistently, ApoE deficient mice show higher serum βHB level than wild-type mice in the fed state and during cold exposure. Our results further demonstrate that the increased βHB production in ApoE deficient adipose precursor cells could be attributed, at least in part, to enhanced Cd36 expression and CD36mediated fatty acid utilization. Our findings uncover a previously uncharacterized role for ApoE in energy homeostasis via its cell-autonomous action in WAT.

Changes in apolipoprotein abundance dominate proteome responses to prolonged fasting in elephant seals

“…They reported that genes encoding metabolic enzymes and extracellular matrix components were significantly downregulated in blubber and skeletal muscle during fasting, suggesting significant metabolic and structural reprogramming of tissues in response to food deprivation (Martinez et al, 2018;Wright et al, 2020). We also previously showed that experimental elevation of cortisol, which normally increases during fasting, resulted in altered expression of genes and abundance of proteins associated with insulin resistance, lipid metabolism, lipid droplet homeostasis and adipogenesis, among other functions, in NES blubber and skeletal muscle (Deyarmin et al, 2020(Deyarmin et al, , 2019Khudyakov et al, 2017Khudyakov et al, , 2015. However, more work is necessary to understand how these metabolic and cellular adjustments are coordinated within and across multiple tissues to maintain metabolic homeostasis during energy-intensive fasting periods in NES.…”

“…APOE expression increases in response to a high-fat diet and decreases in response to caloric restriction and fasting in mice (Huang et al, 2007). Specific APOE ablation in mouse adipose tissue enhances lipolysis, fatty acid oxidation and insulin sensitivity, and increases the expression of adiponectin, an adipokine that stimulates fatty acid catabolism (Jiang et al, 2021). Our previous work showed that adiponectin expression in blubber increases over the molting fast in adult female NES (Khudyakov et al, 2019).…”

Mouse lemur transcriptomic atlas informs primate genes, mutations, physiology, and disease

“…7n). We designate the UCP1-low population (which includes a subpopulation distinguished only by total detected genes and UMI levels per cell but no biologically significant differentially-expressed genes) as "white-like adipocytes" because they are enriched in expression of many white adipocyte genes including APOE, NNAT, and DPT, despite their expression (albeit low) of the brown-defining gene UCP1 [138][139][140] . Further blurring the white-brown distinction, both the classical brown marker CIDEA and the classical white adipokine RBP4 were equally expressed across all adipocytes 141,142 (Fig.…”

“…6n). We designate the UCP1-low population as "white-like" because they show enriched expression of many white adipocyte genes including APOE, NNAT, and DPT, despite their expression (albeit low) of the brown-defining gene UCP1 [105][106][107] . Further blurring the whitebrown distinction, both the classical brown marker CIDEA and the classical white adipokine Tabula Microcebus manuscript 2, p. 27 RBP4 were equally expressed across all adipocytes 108,109 (Fig.…”