Adipocyte Liver Kinase b1 Suppresses Beige Adipocyte Renaissance Through Class IIa Histone Deacetylase 4

Abstract

Uncoupling protein 1+ beige adipocytes are dynamically regulated by environment in rodents and humans; cold induces formation of beige adipocytes, whereas warm temperature and nutrient excess lead to their disappearance. Beige adipocytes can form through de novo adipogenesis; however, how “beiging” characteristics are maintained afterward is largely unknown. In this study, we show that beige adipocytes formed postnatally in subcutaneous inguinal white adipose tissue lost thermogenic gene expression and multilocular morphology at the adult stage, but cold restored their beiging characteristics, a phenomenon termed beige adipocyte renaissance. Ablation of these postnatal beige adipocytes inhibited cold-induced beige adipocyte formation in adult mice. Furthermore, we demonstrated that beige adipocyte renaissance was governed by liver kinase b1 and histone deacetylase 4 in white adipocytes. Although neither presence nor thermogenic function of uncoupling protein 1+ beige adipocytes contributed to metabolic fitness in adipocyte liver kinase b1–deficient mice, our results reveal an unexpected role of white adipocytes in maintaining properties of preexisting beige adipocytes.

Proteome Imbalance of Mitochondrial Electron Transport Chain in Brown Adipocytes Leads to Metabolic Benefits

“…BAT AMPK activity was also diminished in Lkb1 BKO mice (Figures 1A and 1B), further confirming the loss of Lkb1 in BAT. In addition, hematoxylin and eosin (H&E) staining of BAT showed that brown adipocytes were bigger in size (hypertrophy), and a higher percentage of brown adipocytes exhibited unilocu-lar lipid droplet morphology in Lkb1 BKO mice (Figures S1A–S1C), consistent with histological observations in the pan adipocyte-specific Lkb1 knockout mice (Lkb1 AKO ) (Shan et al, 2016; Wang et al, 2017). Lkb1 deficiency in BAT did not affect overall fat mobilization/utilization in these mice; the basal and Forskolin-induced lipolytic activities in BAT and epididymal WAT (eWAT) were similar between control and Lkb1 BKO mice (Figures S1D and S1E).…”

“…For example, the betaless mice were prone to the development of obesity and hepatic steatosis (Bachman et al, 2002). Lkb1 BKO mice did not show any body weight difference up to 5 months of age under normal chow (Figures S3A–S3C); neither did the Lkb1 AKO mice (Wang et al, 2017). We therefore investigated the metabolic phenotypes of Lkb1 BKO mice in response to HFD feeding.…”

“…Notably, beige adipocytes in subcutaneous iWAT were expanded at RT but were absent at thermoneutrality in Tfam BKO mice (Figures S7T–S7V), indicating that beige adipocyte expansion did not contribute to the metabolic benefits under HFD. There was no compensatory expansion of beige adipocytes in iWAT of Lkb1 BKO mice at RT (Wang et al, 2017). In conclusion, our data indicate that specific reduction of mtDNA-encoded ETC genes can lead to ETC proteome imbalance locally in BAT, and systemic metabolic benefits in a thermogenesis-independent manner.…”

“…Previously, we have demonstrated how liver kinase b 1 (Lkb1) suppressed βAR-induced transcription response and regulated the formation of cold-induced brown-like adipocytes in subcutaneous adipose tissue (Wang et al, 2017). Here, we show that brown adipocyte-specific Lkb1 knockout mice (Lkb1 BKO ) had improved metabolic performance under a high-fat diet (HFD) at both RT and thermoneutrality, despite impaired mitochondrial respiration in BAT and defective adaptive thermogenesis.…”

Towards a Better Understanding of Beige Adipocyte Plasticity

“…Chemical denervation with 6-hydroxydopamina, prior to 3-week-old age or prior to cold exposure, impairs beige adipocyte formation, indicating the importance of sympathetic nerves during WAT browning [21]. Previous studies on anatomical positioning of sympathetic nerves in the subcutaneous inguinal white adipose tissue (iWAT), for example, by staining the tyrosine hydrolase + (Th + ) sympathetic nerves in fixed tissues [22,23], lack spatial and temporal precision [21,24,25]. Th + -sympathetic nerves and beige adipocytes are not distributed evenly across iWAT [22], suggesting that anatomic positioning of sympathetic nerves may also contribute to beige adipocyte formation.…”