bims-adipim 2023-08-13 papers

Issue of 2023–08–13
six papers selected by
Matthew C. Sinton, University of Glasgow

Cell Rep. 2023 Aug 04. pii: S2211-1247(23)00960-9. [Epub ahead of print]42(8): 112949

Hypothalamic astrocytic-BMAL1 regulates energy homeostasis in a sex-dependent manner.

María Luengo-Mateos, Antía González-Vila, Nathalia Romanelli Vicente Dragano, Nataliia Ohinska, María Silveira-Loureiro, Marco González-Domínguez, Ánxela Estévez-Salguero, Paula Novelle-Rodríguez, Miguel López, Olga Barca-Mayo.

Here, we demonstrate that hypothalamic astrocytic BMAL1 computes cyclic metabolic information to optimize energetic resources in a sexually dimorphic manner. Knockdown of BMAL1 in female astrocytes leads to negative energy balance and alters basal metabolic cycles without affecting circadian locomotor activity. Thus, astrocytic BMAL1 contributes to the control of energy balance through the modulation of the metabolic rate, hepatic and white adipose tissue lipogenesis, and the activity of brown adipose tissue. Importantly, most of these alterations are specific to hypothalamic astrocytic BMAL1. Moreover, female mice with BMAL1 knockdown in astrocytes exhibited a "male-like" metabolic obese phenotype when fed a high-fat diet. Overall, our results suggest a sexually dimorphic effect of astrocytic BMAL1 on the regulation of energy homeostasis, which may be of interest in the physiopathology of obesity and related comorbidities.

Keywords: CP: Metabolism; CP: Neuroscience

DOI: https://doi.org/10.1016/j.celrep.2023.112949

Nature. 2023 Aug 09.

Lactate limits CNS autoimmunity by stabilizing HIF-1α in dendritic cells.

Dendritic cells (DCs) have a role in the development and activation of self-reactive pathogenic T cells1,2. Genetic variants that are associated with the function of DCs have been linked to autoimmune disorders3,4, and DCs are therefore attractive therapeutic targets for such diseases. However, developing DC-targeted therapies for autoimmunity requires identification of the mechanisms that regulate DC function. Here, using single-cell and bulk transcriptional and metabolic analyses in combination with cell-specific gene perturbation studies, we identify a regulatory loop of negative feedback that operates in DCs to limit immunopathology. Specifically, we find that lactate, produced by activated DCs and other immune cells, boosts the expression of NDUFA4L2 through a mechanism mediated by hypoxia-inducible factor 1α (HIF-1α). NDUFA4L2 limits the production of mitochondrial reactive oxygen species that activate XBP1-driven transcriptional modules in DCs that are involved in the control of pathogenic autoimmune T cells. We also engineer a probiotic that produces lactate and suppresses T cell autoimmunity through the activation of HIF-1α-NDUFA4L2 signalling in DCs. In summary, we identify an immunometabolic pathway that regulates DC function, and develop a synthetic probiotic for its therapeutic activation.

DOI: https://doi.org/10.1038/s41586-023-06409-6

Rev Endocr Metab Disord. 2023 Aug 10.

White adipose tissue mitochondrial bioenergetics in metabolic diseases.

Rugivan Sabaratnam, Didde Riisager Hansen, Per Svenningsen.

White adipose tissue (WAT) is an important endocrine organ that regulates systemic energy metabolism. In metabolically unhealthy obesity, adipocytes become dysfunctional through hypertrophic mechanisms associated with a reduced endocrine function, reduced mitochondrial function, but increased inflammation, fibrosis, and extracellular remodelling. A pathologic WAT remodelling promotes systemic lipotoxicity characterized by fat accumulation in tissues such as muscle and liver, leading to systemic insulin resistance and type 2 diabetes. Several lines of evidence from human and animal studies suggest a link between unhealthy obesity and adipocyte mitochondrial dysfunction, and interventions that improve mitochondrial function may reduce the risk of obesity-associated diseases. This review discusses the importance of mitochondrial function and metabolism in human adipocyte biology and intercellular communication mechanisms within WAT. Moreover, a selected interventional approach for better adipocyte mitochondrial metabolism in humans is reviewed. A greater understanding of mitochondrial bioenergetics in WAT might provide novel therapeutic opportunities to prevent or restore dysfunctional adipose tissue in obesity-associated diseases.

Keywords: Adipose tissue; Extracellular vesicles; Mitochondria; Obesity

DOI: https://doi.org/10.1007/s11154-023-09827-z

Sci Rep. 2023 08 07. 13(1): 12794

Hepcidin deficiency in mice impairs white adipose tissue browning possibly due to a defect in de novo adipogenesis.

Jean-Christophe Deschemin, Céline Ransy, Frédéric Bouillaud, Soonkyu Chung, Bruno Galy, Carole Peyssonnaux, Sophie Vaulont.

The role of iron in the two major sites of adaptive thermogenesis, namely the beige inguinal (iWAT) and brown adipose tissues (BAT) has not been fully understood yet. Body iron levels and distribution is controlled by the iron regulatory peptide hepcidin. Here, we explored iron homeostasis and thermogenic activity in brown and beige fat in wild-type and iron loaded Hepcidin KO mice. Hepcidin-deficient mice displayed iron overload in both iWAT and BAT, and preferential accumulation of ferritin in stromal cells compared to mature adipocytes. In contrast to BAT, the iWAT of Hepcidin KO animals featured with defective thermogenesis evidenced by an altered beige signature, including reduced UCP1 levels and decreased mitochondrial respiration. This thermogenic modification appeared cell autonomous and persisted after a 48 h-cold challenge, a potent trigger of thermogenesis, suggesting compromised de novo adipogenesis. Given that WAT browning occurs in both mice and humans, our results provide physiological results to interrogate the thermogenic capacity of patients with iron overload disorders.

DOI: https://doi.org/10.1038/s41598-023-39305-0

J Immunol. 2023 08 15. 211(4): 518-526

The Dual Role of ACOD1 in Inflammation.

Runliu Wu, Jiao Liu, Daolin Tang, Rui Kang.

Immunometabolism is an interdisciplinary field that focuses on the relationship between metabolic pathways and immune responses. Dysregulated immunometabolism contributes to many pathological settings, such as cytokine storm or immune tolerance. Aconitate decarboxylase 1 (ACOD1, also known as immunoresponsive gene 1), the mitochondrial enzyme responsible for catalyzing itaconate production, was originally identified as a bacterial LPS-inducible gene involved in innate immunity in mouse macrophages. We now know that the upregulation of ACOD1 expression in immune or nonimmune cells plays a context-dependent role in metabolic reprogramming, signal transduction, inflammasome regulation, and protein modification. The emerging function of ACOD1 in inflammation and infection is a double-edged sword. In this review, we discuss how ACOD1 regulates anti-inflammatory or proinflammatory responses in an itaconate-dependent or -independent manner. Further understanding of ACOD1 expression and function may pave the way for the development of precision therapies for inflammatory diseases.

DOI: https://doi.org/10.4049/jimmunol.2300101

Sci Adv. 2023 Aug 11. 9(32): eadg4017

Adipose tissue coregulates cognitive function.

Núria Oliveras-Cañellas, Anna Castells-Nobau, Lisset de la Vega-Correa, Jessica Latorre-Luque, Anna Motger-Albertí, Maria Arnoriaga-Rodriguez, Josep Garre-Olmo, Cristina Zapata-Tona, Clàudia Coll-Martínez, Lluís Ramió-Torrentà, José Maria Moreno-Navarrete, Josep Puig, Francesc Villarroya, Rafel Ramos, Verònica Casadó-Anguera, Elena Martín-García, Rafael Maldonado, Jordi Mayneris-Perxachs, José Manuel Fernández-Real.

Obesity is associated with cognitive decline. Recent observations in mice propose an adipose tissue (AT)-brain axis. We identified 188 genes from RNA sequencing of AT in three cohorts that were associated with performance in different cognitive domains. These genes were mostly involved in synaptic function, phosphatidylinositol metabolism, the complement cascade, anti-inflammatory signaling, and vitamin metabolism. These findings were translated into the plasma metabolome. The circulating blood expression levels of most of these genes were also associated with several cognitive domains in a cohort of 816 participants. Targeted misexpression of candidate gene ortholog in the Drosophila fat body significantly altered flies memory and learning. Among them, down-regulation of the neurotransmitter release cycle-associated gene SLC18A2 improved cognitive abilities in Drosophila and in mice. Up-regulation of RIMS1 in Drosophila fat body enhanced cognitive abilities. Current results show previously unidentified connections between AT transcriptome and brain function in humans, providing unprecedented diagnostic/therapeutic targets in AT.

DOI: https://doi.org/10.1126/sciadv.adg4017