bims-mimbat 2023-01-08 papers

FEBS J. 2023 Jan 03.

Full activation of thermogenesis in brown adipocytes requires Basigin action.

Kaja Rupar, Marie S Isidor, Lidia Argemi-Muntadas, Marina Agueda-Oyarzabal, Kaja Plucińska, Erin L Brown, Matthias Mattanovich, Simone Bossi, Marco Tozzi, David Tandio, Patricia S S Petersen, Tora I Henriksen, Kajetan Trošt, Jacob B Hansen, Zachary Gerhart-Hines, Søren Nielsen, Thomas Moritz, Brice Emanuelli.

Exploring mechanisms responsible for brown adipose tissue's (BAT) high metabolic activity is crucial to exploit its energy dissipating ability for therapeutic purposes. Basigin (Bsg), a multifunctional highly glycosylated transmembrane protein - was recently proposed as one of 98 critical markers allowing to distinguish "white" and "brown" adipocytes, yet its function in thermogenic brown adipocytes is unknown. Here, we report that Bsg is negatively associated with obesity in mice. In contrast, Bsg expression increased in the mature adipocyte fraction of BAT upon cold acclimation. Additionally, Bsg levels were highly induced during brown adipocyte maturation in vitro, and were further increased upon β-adrenergic stimulation in a HIF-1α dependent manner. siRNA-mediated Bsg gene silencing in cultured brown adipocytes did not impact adipogenesis nor mitochondrial function. However, a significant decrease in mitochondrial respiration, lipolysis and Ucp1 transcription was observed in adipocytes lacking Bsg, when activated by norepinephrine. Furthermore, using gas chromatography/mass spectrometry-time-of-flight (GC/MS-TOF) analysis to assess the composition of cellular metabolites, we demonstrate that brown adipocytes lacking Bsg have lower levels of intracellular lactate and acetoacetate (AcAc). Bsg was additionally required to regulate intracellular AcAc and tricarboxylic acid (TCA) cycle intermediate levels in NE-stimulated adipocytes. Our study highlights the critical role of Bsg in active brown adipocytes, possibly by controlling cellular metabolism.

Keywords: Adipocyte; Basigin; Brown adipose tissue; Metabolism; Mitochondria; Thermogenesis; Ucp1

DOI: https://doi.org/10.1111/febs.16716

Nat Commun. 2023 Jan 03. 14(1): 39

The mitochondrial Hsp70 controls the assembly of the F1FO-ATP synthase.

Jiyao Song, Liesa Steidle, Isabelle Steymans, Jasjot Singh, Anne Sanner, Lena Böttinger, Dominic Winter, Thomas Becker.

The mitochondrial F1FO-ATP synthase produces the bulk of cellular ATP. The soluble F1 domain contains the catalytic head that is linked via the central stalk and the peripheral stalk to the membrane embedded rotor of the FO domain. The assembly of the F1 domain and its linkage to the peripheral stalk is poorly understood. Here we show a dual function of the mitochondrial Hsp70 (mtHsp70) in the formation of the ATP synthase. First, it cooperates with the assembly factors Atp11 and Atp12 to form the F1 domain of the ATP synthase. Second, the chaperone transfers Atp5 into the assembly line to link the catalytic head with the peripheral stalk. Inactivation of mtHsp70 leads to integration of assembly-defective Atp5 variants into the mature complex, reflecting a quality control function of the chaperone. Thus, mtHsp70 acts as an assembly and quality control factor in the biogenesis of the F1FO-ATP synthase.

DOI: https://doi.org/10.1038/s41467-022-35720-5

Cell Metab. 2023 Jan 03. pii: S1550-4131(22)00545-9. [Epub ahead of print]35(1): 7-9

Timed feeding aligns the adipocyte clock to optimize thermogenesis when eating a high-fat diet.

Paramita Pati, Jennifer S Pollock, Karen L Gamble.

The timing of food intake is vital for metabolic health in obesity. A recent study in mice from Hepler et al. in Science shows the importance of the adipocyte circadian clock in metabolic health, highlighting the creatine pathway and thermogenesis with the alignment of the timing of high-fat feeding.

DOI: https://doi.org/10.1016/j.cmet.2022.12.008

Nature. 2023 Jan 04.

Metabolic regulation of species-specific developmental rates.

Margarete Diaz-Cuadros, Teemu P Miettinen, Owen S Skinner, Dylan Sheedy, Carlos Manlio Díaz-García, Svetlana Gapon, Alexis Hubaud, Gary Yellen, Scott R Manalis, William M Oldham, Olivier Pourquié.

Animals display substantial inter-species variation in the rate of embryonic development despite a broad conservation of the overall sequence of developmental events. Differences in biochemical reaction rates, including the rates of protein production and degradation, are thought to be responsible for species-specific rates of development1-3. However, the cause of differential biochemical reaction rates between species remains unknown. Here, using pluripotent stem cells, we have established an in vitro system that recapitulates the twofold difference in developmental rate between mouse and human embryos. This system provides a quantitative measure of developmental speed as revealed by the period of the segmentation clock, a molecular oscillator associated with the rhythmic production of vertebral precursors. Using this system, we show that mass-specific metabolic rates scale with the developmental rate and are therefore higher in mouse cells than in human cells. Reducing these metabolic rates by inhibiting the electron transport chain slowed down the segmentation clock by impairing the cellular NAD+/NADH redox balance and, further downstream, lowering the global rate of protein synthesis. Conversely, increasing the NAD+/NADH ratio in human cells by overexpression of the Lactobacillus brevis NADH oxidase LbNOX increased the translation rate and accelerated the segmentation clock. These findings represent a starting point for the manipulation of developmental rate, with multiple translational applications including accelerating the differentiation of human pluripotent stem cells for disease modelling and cell-based therapies.

DOI: https://doi.org/10.1038/s41586-022-05574-4