bims-aditis 2022-01-09 papers

Issue of 2022‒01‒09
five papers selected by
Matthew C. Sinton, University of Glasgow

Mol Cell Endocrinol. 2022 Jan 04. pii: S0303-7207(21)00386-5. [Epub ahead of print] 111542

Inhibitory effect of androgens on white adipose tissue thermogenic capacity.

Alejandro Ezequiel Harnichar, María Guillermina Zubiría, Alejandra Paula Giordano, Ignacio Miguel, María Amanda Rey, Eduardo Spinedi, Andrés Giovambattista.

White adipose tissue (WAT) browning has gained interest due to its impact in obesity. Here, we evaluated the effect of androgens on the Ucp1-dependent thermogenic process from inguinal (IAT) and retroperitoneal (RPAT) WAT. Surgically androgens depleted rats (ODX) showed basal thermogenic activation (room temperature) in both WAT depots, which expressed higher levels of Ucp1, Prdm16 and Pgc1a. WAT pads from ODX cold-exposed rats (ODX-C) expressed increased levels of Ucp1 and Pgc1a and showed high UCP1 protein content. In primary beige adipocyte cultures, testosterone decreased the mitochondrial marker Cox8b and mitochondrial content. Finally, testosterone and dihydrotestosterone (DHT) decreased the expression of Ucp1, Pcg1a and Prdm16 in forskolin-stimulated beige adipocytes, an effect that was prevented by the antiandrogen flutamide. In conclusion, androgen deficient rats developed WAT depots with enhanced basal and cold-stimulated thermogenic activity. Additionally, in vitro androgen treatments inhibited the thermogenic program, effect which was mediated by the androgen receptor pathway.

Keywords: Adipocytes; Browning; Testosterone

DOI: https://doi.org/10.1016/j.mce.2021.111542

Front Cell Dev Biol. 2021 ;9 786129

Origin and Development of the Adipose Tissue, a Key Organ in Physiology and Disease.

Esmeralda Parra-Peralbo, Ana Talamillo, Rosa Barrio.

Adipose tissue is a dynamic organ, well known for its function in energy storage and mobilization according to nutrient availability and body needs, in charge of keeping the energetic balance of the organism. During the last decades, adipose tissue has emerged as the largest endocrine organ in the human body, being able to secrete hormones as well as inflammatory molecules and having an important impact in multiple processes such as adipogenesis, metabolism and chronic inflammation. However, the cellular progenitors, development, homeostasis and metabolism of the different types of adipose tissue are not fully known. During the last decade, Drosophila melanogaster has demonstrated to be an excellent model to tackle some of the open questions in the field of metabolism and development of endocrine/metabolic organs. Discoveries ranged from new hormones regulating obesity to subcellular mechanisms that regulate lipogenesis and lipolysis. Here, we review the available evidences on the development, types and functions of adipose tissue in Drosophila and identify some gaps for future research. This may help to understand the cellular and molecular mechanism underlying the pathophysiology of this fascinating key tissue, contributing to establish this organ as a therapeutic target.

Keywords: BAT; WAT; adepithelial cells; adipose stem cells; adipose tissue; beige adipocytes; drosophila; fat body development

DOI: https://doi.org/10.3389/fcell.2021.786129

Cell Mol Immunol. 2022 Jan 05.

Diet, lipids, and antitumor immunity.

Hannah Prendeville, Lydia Lynch.

Tumour growth and dissemination is largely dependent on nutrient availability. It has recently emerged that the tumour microenvironment is rich in a diverse array of lipids that increase in abundance with tumour progression and play a role in promoting tumour growth and metastasis. Here, we describe the pro-tumorigenic roles of lipid uptake, metabolism and synthesis and detail the therapeutic potential of targeting lipid metabolism in cancer. Additionally, we highlight new insights into the distinct immunosuppressive effects of lipids in the tumour microenvironment. Lipids threaten an anti-tumour environment whereby metabolic adaptation to lipid metabolism is linked to immune dysfunction. Finally, we describe the differential effects of commondietary lipids on cancer growth which may uncover a role for specific dietary regimens in association with traditional cancer therapies. Understanding the relationship between dietary lipids, tumour, and immune cells is important in the context of obesity which may reveal a possibility to harness the diet in the treatment of cancers.

Keywords: Lipids; anti-tumour immunity; cancer; obesity; β-oxidation

DOI: https://doi.org/10.1038/s41423-021-00781-x

Cell Metab. 2022 Jan 04. pii: S1550-4131(21)00623-9. [Epub ahead of print]34(1): 171-183.e6

FGF1 and insulin control lipolysis by convergent pathways.

Inexorable increases in insulin resistance, lipolysis, and hepatic glucose production (HGP) are hallmarks of type 2 diabetes. Previously, we showed that peripheral delivery of exogenous fibroblast growth factor 1 (FGF1) has robust anti-diabetic effects mediated by the adipose FGF receptor (FGFR) 1. However, its mechanism of action is not known. Here, we report that FGF1 acutely lowers HGP by suppressing adipose lipolysis. On a molecular level, FGF1 inhibits the cAMP-protein kinase A axis by activating phosphodiesterase 4D (PDE4D), which separates it mechanistically from the inhibitory actions of insulin via PDE3B. We identify Ser44 as an FGF1-induced regulatory phosphorylation site in PDE4D that is modulated by the feed-fast cycle. These findings establish the FGF1/PDE4 pathway as an alternate regulator of the adipose-HGP axis and identify FGF1 as an unrecognized regulator of fatty acid homeostasis.

Keywords: FGF1; PDE4; cAMP; hepatic glucose production; insulin; lipolysis; type 2 diabetes

DOI: https://doi.org/10.1016/j.cmet.2021.12.004

J Biol Chem. 2021 Dec 29. pii: S0021-9258(21)01364-8. [Epub ahead of print] 101554

Mitochondrial Pyruvate Carrier Inhibitors Improve Metabolic Parameters in Diet-Induced Obese Mice.

Wesley T Hodges, Chaowapong Jarasvaraparn, Daniel Ferguson, Kristine Griffett, Lauren E Gill, Yana Chen, Ma Xenia G Ilagan, Lamees Hegazy, Bahaa Elgendy, Kevin Cho, Gary J Patti, Kyle S McCommis, Brian N Finck.

The mitochondrial pyruvate carrier (MPC) is an inner mitochondrial membrane complex that plays a critical role in intermediary metabolism. Inhibition of the MPC, especially in liver, may have efficacy for treating type 2 diabetes mellitus. Herein, we examined the anti-diabetic effects of zaprinast and 7ACC2, small molecules which have been previously reported to act as MPC inhibitors. Both compounds activated a bioluminescence resonance energy transfer (BRET)-based MPC reporter assay (reporter sensitive to pyruvate; RESPYR) and potently inhibited pyruvate-mediated respiration in isolated mitochondria. Furthermore, zaprinast and 7ACC2 acutely improved glucose tolerance in diet-induced obese mice in vivo. Although some findings were suggestive of improved insulin sensitivity, hyperinsulinemic-euglycemic clamp studies did not detect enhanced insulin action in response to 7ACC2 treatment. Rather, our data suggest acute glucose-lowering effects of MPC inhibition may be due to suppressed hepatic gluconeogenesis. Finally, we used RESPYR to screen a chemical library (Pharmakon 1600) of drugs and identified 35 potentially novel MPC modulators. Using available evidence, we generated a pharmacophore model to prioritize which hits to pursue. Our analysis revealed carsalam and six quinolone antibiotics, as well as 7ACC1, share a common pharmacophore with 7ACC2. We validated that these compounds are novel inhibitors of the MPC and suppress hepatocyte glucose production, and demonstrated that one quinolone (nalidixic acid) improved glucose tolerance in obese mice. In conclusion, these data demonstrate the feasibility of therapeutic targeting of the MPC for treating diabetes and provide scaffolds that can be used to develop potent and novel classes of MPC inhibitors.

Keywords: diabetes; gluconeogenesis; metabolic disease; mitochondrial metabolism; pyruvate

DOI: https://doi.org/10.1016/j.jbc.2021.101554