The short-chain fatty acid receptors Gpr41/43 regulate bone mass by promoting adipogenic differentiation of mesenchymal stem cells.

Bone is a dynamic tissue that is constantly remodeled throughout adult life. Recently, it has been shown that bone turnover decreases shortly after food consumption. This process has been linked to the fermentation of non-digestible food ingredients such as inulin by gut microbes, which results in the production of the short-chain fatty acids (SCFAs) acetate, propionate and butyrate.

An efficient AAV vector system of Rec2 serotype for intravenous injection to study metabolism in brown adipocytes in vivo.

Objective: Recombinant adeno-associated virus (rAAV) vectors are powerful tools for the sustained expression of proteins in vivo and have been successfully used for mechanistic studies in mice. A major challenge associated with this method is to obtain tissue specificity and high expression levels without need of local virus administration.

Methods: To achieve this goal for brown adipose tissue (BAT), we developed a rAAV vector for intravenous bolus injection, which includes an expression cassette comprising an uncoupling protein-1 enhancer-promoter for transcription in brown adipocytes and miR122 target sequences for suppression of expression in the liver, combined with packaging in serotype Rec2 capsid protein.

The TRPM2 ion channel regulates metabolic and thermogenic adaptations in adipose tissue of cold-exposed mice.

Introduction: During thermogenesis, adipose tissue (AT) becomes more active and enhances oxidative metabolism. The promotion of this process in white AT (WAT) is called "browning" and, together with the brown AT (BAT) activation, is considered as a promising approach to counteract obesity and metabolic diseases. Transient receptor potential cation channel, subfamily M, member 2 (TRPM2), is an ion channel that allows extracellular Ca influx into the cytosol, and is gated by adenosine diphosphate ribose (ADPR), produced from NAD degradation.

CD73-dependent generation of extracellular adenosine by vascular endothelial cells modulates lipogenesis in adipose tissue.

Next to white and brown adipocytes present in white and brown adipose tissue (WAT, BAT), vascular endothelial cells, tissue-resident macrophages and other immune cells have important roles in maintaining adipose tissue homeostasis but also contribute to the etiology of obesity-associated chronic inflammatory metabolic diseases. In addition to hormonal signals such as insulin and norepinephrine, extracellular adenine nucleotides modulate lipid storage, fatty acid release and thermogenic responses in adipose tissues. The complex regulation of extracellular adenine nucleotides involves a network of ectoenzymes that convert ATP via ADP and AMP to adenosine.

EPAC1 enhances brown fat growth and beige adipogenesis.

Brown adipose tissue (BAT) is a central thermogenic organ that enhances energy expenditure and cardiometabolic health. However, regulators that specifically increase the number of thermogenic adipocytes are still an unmet need. Here, we show that the cAMP-binding protein EPAC1 is a central regulator of adaptive BAT growth.

Apoptotic brown adipocytes enhance energy expenditure via extracellular inosine.

Brown adipose tissue (BAT) dissipates energy and promotes cardiometabolic health. Loss of BAT during obesity and ageing is a principal hurdle for BAT-centred obesity therapies, but not much is known about BAT apoptosis. Here, untargeted metabolomics demonstrated that apoptotic brown adipocytes release a specific pattern of metabolites with purine metabolites being highly enriched.

Role of Endothelial Cell Lipoprotein Lipase for Brown Adipose Tissue Lipid and Glucose Handling.

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.

Lysosomal acid lipase promotes endothelial proliferation in cold-activated adipose tissue.

Oxidative tissues such as brown adipose tissue and muscle internalize large amounts of circulating lipids and glucose as energy source. Endothelial cells (ECs) provide a platform for regulated transport and processing of blood-borne nutrients. Next to this role, it has become recognized that intercellular crosstalk between ECs and underlying parenchymal cells is indispensable for maintenance of tissue homoeostasis.

Replication of SARS-CoV-2 in adipose tissue determines organ and systemic lipid metabolism in hamsters and humans.

Zickler et al. describe SARS-CoV-2 RNA in post-mortem samples of human adipose tissue. In the hamster model, SARS-CoV-2 propagation in adipose tissue leads to specific changes in lipid metabolism, which are reflected in lipidome patterns of hamster and human plasma.

TFEB deficiency attenuates mitochondrial degradation upon brown adipose tissue whitening at thermoneutrality.

Objective: Brown adipose tissue (BAT) thermogenesis offers the potential to improve metabolic health in mice and humans. However, humans predominantly live under thermoneutral conditions, leading to BAT whitening, a reduction in BAT mitochondrial content and metabolic activity. Recent studies have established mitophagy as a major driver of mitochondrial degradation in the whitening of thermogenic brite/beige adipocytes, yet the pathways mediating mitochondrial breakdown in whitening of classical BAT remain largely elusive.

Endogenous Fatty Acid Synthesis Drives Brown Adipose Tissue Involution.

Thermoneutral conditions typical for standard human living environments result in brown adipose tissue (BAT) involution, characterized by decreased mitochondrial mass and increased lipid deposition. Low BAT activity is associated with poor metabolic health, and BAT reactivation may confer therapeutic potential. However, the molecular drivers of this BAT adaptive process in response to thermoneutrality remain enigmatic.

Lysosomal lipoprotein processing in endothelial cells stimulates adipose tissue thermogenic adaptation.

In response to cold exposure, thermogenic adipocytes internalize large amounts of fatty acids after lipoprotein lipase-mediated hydrolysis of triglyceride-rich lipoproteins (TRL) in the capillary lumen of brown adipose tissue (BAT) and white adipose tissue (WAT). Here, we show that in cold-exposed mice, vascular endothelial cells in adipose tissues endocytose substantial amounts of entire TRL particles. These lipoproteins subsequently follow the endosomal-lysosomal pathway, where they undergo lysosomal acid lipase (LAL)-mediated processing.

The P2X7 ion channel is dispensable for energy and metabolic homeostasis of white and brown adipose tissues.

Several studies suggest a role of extracellular adenine nucleotides in regulating adipose tissue functions via the purinergic signaling network. Metabolic studies in mice with global deletion of the purinergic receptor P2X7 on the C57BL/6 background indicate that this receptor has only a minor role in adipose tissue for diet-induced inflammation or cold-triggered thermogenesis. However, recent data show that a polymorphism (P451L) present in C57BL/6 mice attenuates P2X7 receptor function, whereas BALB/c mice express the fully functional P451 allele.