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

Abstract

SUMMARY Brown adipose tissue (BAT) thermogenesis is critical for thermoregulation and contributes to total energy expenditure. However, whether BAT has non-thermogenic functions is largely unknown. Here, we describe that BAT-specific liver kinase b1 knockout (Lkb1BKO) mice exhibited impaired BAT mitochondrial respiration and thermogenesis but reduced adiposity and liver triglyceride accumulation under high-fat-diet feeding at room temperature. Importantly, these metabolic benefits were also present in Lkb1BKO mice at thermoneutrality, where BAT thermogenesis was not required. Mechanistically, decreased mRNA levels of mtDNA-encoded electron transport chain (ETC) subunits and ETC proteome imbalance led to defective BAT mitochondrial respiration in Lkb1BKO mice. Furthermore, reducing mtDNA gene expression directly in BAT by removing mitochondrial transcription factor A (Tfam) in BAT also showed ETC proteome imbalance and the trade-off between BAT thermogenesis and systemic metabolism at room temperature and thermo-neutrality. Collectively, our data demonstrate that ETC proteome imbalance in BAT regulates systemic metabolism independently of thermogenesis.

Adipocyte HDAC4 activation leads to beige adipocyte expansion and reduced adiposity

“…We have employed pan adipocyte-specific Adiponectin-Cre and brown/beige adipocyte-specific Ucp1-Cre to investigate roles of liver kinase b1 (Lkb1) in adipocytes to demonstrate that Lkb1 regulates two distinct pathways in brown and beige adipocytes. In brown adipocytes, Lkb1 appears to govern thermogenic capacity independently of HDAC4 (Masand et al, 2018); but in white adipocytes, it controls HDAC4 activity (through Salt-inducible kinases/SIKs) to regulate beige adipocyte renaissance non-cell autonomously (Wang et al, 2017). We reasoned that HDAC4 activation in white adipocytes could promote beige adipocyte renaissance in iWAT without affecting adaptive thermogenesis in BAT, and this unique requirement of HDAC4 for beige adipocyte renaissance could enable us to address beige adipocyte specific function in energy homeostasis.…”

Host-dependent induction of disease tolerance to infection by tetracycline antibiotics

“…Pioneer work in C. elegans revealed that mild perturbations in mitochondrial function induced both by genetic defects in the electron transfer chain (ETC) (Dillin et al, 2002) or inhibition of mitochondrial protein synthesis (Houtkooper et al, 2013) resulted in extended lifespan. In mice, several studies have documented metabolic benefits arising from inhibition of ETC activity in the context of obesity and insulin resistance (Chung et al, 2017;Masand et al, 2018;Pospisilik et al, 2007) with no significant effects in longevity (Deepa et al, 2018). While the molecular mechanisms of mitochondrial stress responses remain poorly understood in mammals, it is generally accepted that perturbations in mitochondrial function involve: 1) retrograde signaling to the nucleus, which activates a transcriptional program known as the mitochondrial unfolded protein response (UPR mt ) (Fiorese et al, 2016;Houtkooper et al, 2013), and 2) metabolic adaptation, which may increase fitness in adverse conditions (Masand et al, 2018).…”

“…In mice, several studies have documented metabolic benefits arising from inhibition of ETC activity in the context of obesity and insulin resistance (Chung et al, 2017;Masand et al, 2018;Pospisilik et al, 2007) with no significant effects in longevity (Deepa et al, 2018). While the molecular mechanisms of mitochondrial stress responses remain poorly understood in mammals, it is generally accepted that perturbations in mitochondrial function involve: 1) retrograde signaling to the nucleus, which activates a transcriptional program known as the mitochondrial unfolded protein response (UPR mt ) (Fiorese et al, 2016;Houtkooper et al, 2013), and 2) metabolic adaptation, which may increase fitness in adverse conditions (Masand et al, 2018). Besides mitochondria, perturbation of other core cellular functions such as insulin/insulin growth-factor signaling (Kenyon et al, 1993), mRNA translation (Govindan et al, 2015), and ER protein homeostasis (Fouillet et al, 2012) have shown beneficial effects in numerous experimental models.…”

Towards a Better Understanding of Beige Adipocyte Plasticity

“…Tissue specificity of available Cre lines has been summarized [74][75][76]. Caution should be taken to link the WAT browning to the systemic metabolism in mouse models using Adiponectin, Prx1 or Fabp4, or Ucp1 enhancer/promoter-driven gene deletion or overexpression [24,25,77,78]. With this notion in mind, the maintenance of the thermogenically active Ucp1 + -lineage adipocytes in iWAT has been investigated in several groups.…”

“…Consequently, it will be unlikely that metabolic benefits are contributed by thermogenic activity from these bona fide beige adipocytes, because they are neither multilocular nor Ucp1-positive after long-term HFD. For example, very few mouse models show persistent WAT browning after long-term HFD, with the exception of the brown adipocyte-specific Tle3 and Tfam knockout mice and global Irf3 knockout mice (Table 1) [77,88,89]. The lack of stable and thermogenically active beige adipocytes under obesogenic conditions still represents a significant obstacle in advancing beige adipocyte-based therapies, which also reflects an incomplete understanding of the mechanisms governing beige adipocyte formation and function, despite over 30 years of research in this field.…”