bims-mimbat Biomed News
on Mitochondrial metabolism in brown adipose tissue
Issue of 2022‒04‒17
nine papers selected by
José Carlos de Lima-Júnior
University of California San Francisco

  1. J Exp Med. 2022 May 02. pii: e20212491. [Epub ahead of print]219(5):
      Metabolically beneficial beige adipocytes offer tremendous potential to combat metabolic diseases. The folliculin interacting protein 1 (FNIP1) is implicated in controlling cellular metabolism via AMPK and mTORC1. However, whether and how FNIP1 regulates adipocyte browning is unclear. Here, we demonstrate that FNIP1 plays a critical role in controlling adipocyte browning and systemic glucose homeostasis. Adipocyte-specific ablation of FNIP1 promotes a broad thermogenic remodeling of adipocytes, including increased UCP1 levels, high mitochondrial content, and augmented capacity for mitochondrial respiration. Mechanistically, FNIP1 binds to and promotes the activity of SERCA, a main Ca2+ pump responsible for cytosolic Ca2+ removal. Loss of FNIP1 resulted in enhanced intracellular Ca2+ signals and consequential activation of Ca2+-dependent thermogenic program in adipocytes. Furthermore, mice lacking adipocyte FNIP1 were protected against high-fat diet-induced insulin resistance and liver steatosis. Thus, these findings reveal a pivotal role of FNIP1 as a negative regulator of beige adipocyte thermogenesis and unravel an intriguing functional link between intracellular Ca2+ dynamics and adipocyte browning.
  2. J Exp Med. 2022 May 02. pii: e20220382. [Epub ahead of print]219(5):
      In this issue of Journal of Experimental Medicine, Yin et al. (2022. J. Exp. Med. discover that loss of FNIP1 is associated with browning of white adipose tissue, which they propose is driven by decreased calcium uptake into the ER.
  3. Front Physiol. 2022 ;13 859671
      Cold-induced activation of brown adipose tissue (BAT) has an important impact on systemic lipoprotein metabolism by accelerating the processing of circulating triglyceride-rich lipoproteins (TRL). Lipoprotein lipase (LPL) expressed by adipocytes is translocated via endothelial to the capillary lumen, where LPL acts as the central enzyme for the vascular lipoprotein processing. Based on preliminary data showing that LPL is not only expressed in adipocytes but also in endothelial cells of cold-activated BAT, we aimed to dissect the relevance of endothelial versus adipocyte LPL for lipid and energy metabolism in the context of adaptive thermogenesis. By metabolic studies we found that cold-induced triglyceride uptake into BAT, lipoprotein disposal, glucose uptake and adaptive thermogenesis were not impaired in mice lacking Lpl exclusively in endothelial cells. This finding may be explained by a compensatory upregulation in the expression of adipocyte-derived Lpl and endothelial lipase (Lipg).
    Keywords:  adipocytes; adipose tissue; de novo lipogenesis; endothelial cells; lipoprotein lipase; lipoproteins; thermogenesis; triglycerides
  4. Cell Rep. 2022 Apr 12. pii: S2211-1247(22)00319-9. [Epub ahead of print]39(2): 110575
      Human brown adipose tissue (BAT) undergoes progressive involution. This involution process is not recapitulated in rodents, and the underlying mechanisms are poorly understood. Here we show that the interscapular BAT (iBAT) of rabbits whitens rapidly during early adulthood. The transcriptomic remodeling and identity switch of mature adipocytes are accompanied by loss of brown adipogenic competence of progenitors. Single-cell RNA sequencing reveals that rabbit and human iBAT progenitors highly express the FSTL1 gene. When iBAT involutes in rabbits, adipocyte progenitors reduce FSTL1 expression and are refractory to brown adipogenic recruitment. Conversely, FSTL1 is constitutively expressed in mouse iBAT to sustain WNT signaling and prevent involution. Progenitor incompetence and iBAT paucity can be induced in mice by genetic deletion of the Fstl1 gene or ablation of Fstl1+ progenitors. Our results highlight the hierarchy and dynamics of the BAT progenitor compartment and implicate the functional incompetence of FSTL1-expressing progenitors in BAT involution.
    Keywords:  Brown adipose tissue; CP: Metabolism; FSTL1; UCP1; Wnt signaling; adipose progenitor cells; aging; involution; single-cell RNA sequencing; thermogenesis; whitening
  5. Adipocyte. 2022 Dec;11(1): 213-226
      The mechanism of insulin signaling on browning of white preadipocytes remains unclear. Human and mouse primary subcutaneous white preadipocytes (hsASCs and WT lean and obese msASCs, respectively) were induced to transdifferentiate into beige adipocytes under conditions of intact or blocked insulin signaling, respectively. Level of phosphoinositide-3-kinase (PI3K) after induction of beige adipocytes under conditions of normal insulin signaling, phosphorylated protein kinase B (pAKT), peroxisome proliferator-activated receptor γ coactivator-1 alpha (PGC-1α), zinc-fifinger transcriptional factor PRD1-BF1-RIZ1 homologous domain-containing protein 16 (PRDM16), uncoupling protein 1 (UCP1), peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer binding protein beta (C/EBPβ) were significantly increased. Conversely, when insulin signaling is incompletely inhibited, the expression of the thermogenic and adipogenic factors is significantly reduced, with obvious impairment of adipogenesis. However, phosphorylation level of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) and expression level of sirtuin type 1 (SIRT1) had increased. These white preadipocytes from different donors showed similar dynamic change in morphology and molecular levels during the browning. The present data indicate that insulin signaling plays a important role in regulation of browning of hsASCs and msASCs through PI3K-AKT-UCP1 signaling pathway. The insulin-AMPK-SIRT1 pathway was also involved in the adipocytes browning, while its effect is limited.
    Keywords:  AKT; Insulin signalling; UCP1; browning; white preadipocytes
  6. Mol Metab. 2022 Apr 09. pii: S2212-8778(22)00066-7. [Epub ahead of print] 101497
      Brown adipose tissue (BAT) burns fatty acids (FAs) to produce heat, and shows diurnal oscillation in glucose and triglyceride (TG)-derived FA-uptake, peaking around wakening. To gain insight in the diurnal regulation of metabolic BAT activity, we employed RNA-sequencing and lipidomics in murine BAT and identified pronounced enrichment of oscillating genes involved in extracellular lipolysis accompanied by oscillations of FA and monoacylglycerol content. This coincided with peak lipoprotein lipase (Lpl) expression, and was predicted to be driven by peroxisome proliferator-activated receptor gamma (PPARγ) activity. Chromatin immunoprecipitation (ChIP)-sequencing for PPARγ confirmed oscillation in binding of PPARγ to Lpl. Of the known LPL-modulators, angiopoietin-like 4 (Angptl4) showed the largest diurnal amplitude opposite to Lpl, and both Angptl4 knockout and overexpression attenuated oscillations of LPL and TG-derived FA-uptake by BAT. Our findings highlight involvement of PPARγ and a crucial role of ANGPTL4 in mediating the diurnal oscillation of TG-derived FA-uptake by BAT, and imply that time of day is essential when targeting LPL activity in BAT to improve metabolic health.
    Keywords:  Angiopoietin-Like 4; Brown adipose tissue; Circadian/Diurnal Rhythms; Lipoprotein Lipase; Peroxisome Proliferator-Activated Receptor Gamma; Transcriptomics
  7. Life Sci. 2022 Apr 07. pii: S0024-3205(22)00240-5. [Epub ahead of print] 120540
      AIMS: In mammals, heat stress (HS) from high-temperature environments has multiple adverse effects on the well-being of the organism. Brown adipose tissue (BAT) is a thermogenesis tissue that protects against obesity, and as an endocrine organ that regulates the systemic metabolism, but it is unclear how heat stress affects BAT in normal and obese subjects. Understanding the transcriptomic profiles and lipidomics of BAT upon heat exposure provides insights into the adaptive changes associated with this process.MATERIALS AND METHODS: We constructed heat treatment (40 °C, 4 h) models for normal and obese mice, observed the effect of heat treatment on interscapular BAT (iBAT) and performed an assay for iBAT with RNA-seq and lipidomics to compare transcriptional programs and lipid dynamics.
    KEY FINDINGS: In normal mice, heat treatment caused an iBAT damage by decreasing the expression of genes involved in thermogenesis, adipogenesis and lipid metabolism. Furthermore, HS disturbed the acyl-chain composition of triacylglycerols (TAGs) and glycerophospholipids (PEs, PCs and CLs), accelerated the production of cholesterol esters, and caused the formation of giant lipid droplets rich in cholesterol esters in iBAT. Unexpectedly, in obese mice, heat treatment had a smaller effect on iBAT by improving the composition of the saturated glycerolipids, PEs and PCs and increasing the proportion of oxidized lipid in lipid droplets.
    SIGNIFICANCE: Our findings proved lipid droplets participated in the regulation of lipid components of iBAT in normal and obese mice after heat treatment, which provided a new view for the understanding of the adaptation of iBAT to high-temperature environments.
    Keywords:  Heat exposure; Hyperthermia adaptation; Lipid droplets; Obesity; iBAT damage
  8. Am J Physiol Regul Integr Comp Physiol. 2022 Apr 12.
      Despite many decades of research examining thermoregulatory responses under varying cold stresses in humans, very little is known about the variability in metabolic heat production and shivering activity. Here, we used a novel closed-loop mean skin temperature clamping technique with a liquid-conditioned suit to isolate the effects of mean skin temperature on the subjective evaluation of thermal sensation, heat production, shivering responses, and oxidative fuel selection in young, lean and healthy men (n = 12) and women (n = 12). Our results showed a skin temperature-dependent increase in metabolic heat production (5.2±1.0 kJ/min, 5.9±1.0 kJ/min and 7.0±1.0 kJ/min with skin temperature maintained at 31°C, 29°C and 27°C, respectively; P< 0.0001) and shivering intensity in both men and women (0.6±0.1 %MVC, 1.1±0.4 %MVC and 2.5±0.7 %MVC, respectively; P<0.0001), including sex-dependent differences in heat production at all three temperatures (P < 0.005). Even when controlling for lean body mass and fat mass, sex differences persisted (P = 0.048 and P = 0.004, respectively), whereas controlling for differences in body surface area eliminated these differences. Interestingly, there were no sex differences in the cold-induced change in thermogenesis. Despite clamping skin temperature, there was tremendous variability in the rate of heat production and shivering intensity. Collectively this data suggests that many of the inter-individual differences in thermogenesis and shivering may be explained by differences in morphology and body composition.
    Keywords:  Cold exposure; Fuel selection; Shivering; Thermogenesis; energy metabolism