bims-aditis 2022-03-20 papers

Issue of 2022–03–20
six papers selected by
Matthew C. Sinton, University of Glasgow

Open Biol. 2022 Mar;12(3): 210345

Visualization of sympathetic neural innervation in human white adipose tissue.

Aliki Perdikari, Tessa Cacciottolo, Elana Henning, Edson Mendes de Oliveira, Julia M Keogh, I Sadaf Farooqi.

Obesity, defined as an excess of adipose tissue that adversely affects health, is a major cause of morbidity and mortality. However, to date, understanding the structure and function of human adipose tissue has been limited by the inability to visualize cellular components due to the innate structure of adipocytes, which are characterized by large lipid droplets. Combining the iDISCO and the CUBIC protocols for whole tissue staining and optical clearing, we developed a protocol to enable immunostaining and clearing of human subcutaneous white adipose tissue (WAT) obtained from individuals with severe obesity. We were able to perform immunolabelling of sympathetic nerve terminals in whole WAT and subsequent optical clearing by eliminating lipids to render the opaque tissue completely transparent. We then used light sheet confocal microscopy to visualize sympathetic innervation of human WAT from obese individuals in a three-dimensional manner. We demonstrate the visualization of sympathetic nerve terminals in human WAT. This protocol can be modified to visualize other structures such as blood vessels involved in the development, maintenance and function of human adipose tissue in health and disease.

Keywords: human adipose tissue; obesity; sympathetic innervation; three-dimensional microscopy; whole tissue immunolabelling

DOI: https://doi.org/10.1098/rsob.210345

Nature. 2022 Mar 16.

A single-cell atlas of human and mouse white adipose tissue.

White adipose tissue, once regarded as morphologically and functionally bland, is now recognized to be dynamic, plastic and heterogenous, and is involved in a wide array of biological processes including energy homeostasis, glucose and lipid handling, blood pressure control and host defence1. High-fat feeding and other metabolic stressors cause marked changes in adipose morphology, physiology and cellular composition1, and alterations in adiposity are associated with insulin resistance, dyslipidemia and type 2 diabetes2. Here we provide detailed cellular atlases of human and mouse subcutaneous and visceral white fat at single-cell resolution across a range of body weight. We identify subpopulations of adipocytes, adipose stem and progenitor cells, vascular and immune cells and demonstrate commonalities and differences across species and dietary conditions. We link specific cell types to increased risk of metabolic disease and provide an initial blueprint for a comprehensive set of interactions between individual cell types in the adipose niche in leanness and obesity. These data comprise an extensive resource for the exploration of genes, traits and cell types in the function of white adipose tissue across species, depots and nutritional conditions.

DOI: https://doi.org/10.1038/s41586-022-04518-2

Immune Netw. 2022 Feb;22(1): e13

The Role of T Cells in Obesity-Associated Inflammation and Metabolic Disease.

Chan-Su Park, Nilabh Shastri.

Chronic inflammation plays a critical role in the development of obesity-associated metabolic disorders such as insulin resistance. Obesity alters the microenvironment of adipose tissue and the intestines from anti-inflammatory to pro-inflammatory, which promotes low grade systemic inflammation and insulin resistance in obese mice. Various T cell subsets either help maintain metabolic homeostasis in healthy states or contribute to obesity-associated metabolic syndromes. In this review, we will discuss the T cell subsets that reside in adipose tissue and intestines and their role in the development of obesity-induced systemic inflammation.

Keywords: Insulin resistance; Metabolic diseases; Obese mice; Obesity-associated inflammation; T cells

DOI: https://doi.org/10.4110/in.2022.22.e13

Front Physiol. 2022 ;13 826314

The Molecular Brakes of Adipose Tissue Lipolysis.

Yongguo Li, Zhen Li, Devi Anggraini Ngandiri, Mireia Llerins Perez, Alexander Wolf, Yuanyuan Wang.

Adaptation to changes in energy availability is pivotal for the survival of animals. Adipose tissue, the body's largest reservoir of energy and a major source of metabolic fuel, exerts a buffering function for fluctuations in nutrient availability. This functional plasticity ranges from energy storage in the form of triglycerides during periods of excess energy intake to energy mobilization via lipolysis in the form of free fatty acids for other organs during states of energy demands. The subtle balance between energy storage and mobilization is important for whole-body energy homeostasis; its disruption has been implicated as contributing to the development of insulin resistance, type 2 diabetes and cancer cachexia. As a result, adipocyte lipolysis is tightly regulated by complex regulatory mechanisms involving lipases and hormonal and biochemical signals that have opposing effects. In thermogenic brown and brite adipocytes, lipolysis stimulation is the canonical way for the activation of non-shivering thermogenesis. Lipolysis proceeds in an orderly and delicately regulated manner, with stimulation through cell-surface receptors via neurotransmitters, hormones, and autocrine/paracrine factors that activate various intracellular signal transduction pathways and increase kinase activity. The subsequent phosphorylation of perilipins, lipases, and cofactors initiates the translocation of key lipases from the cytoplasm to lipid droplets and enables protein-protein interactions to assemble the lipolytic machinery on the scaffolding perilipins at the surface of lipid droplets. Although activation of lipolysis has been well studied, the feedback fine-tuning is less well appreciated. This review focuses on the molecular brakes of lipolysis and discusses some of the divergent fine-tuning strategies in the negative feedback regulation of lipolysis, including delicate negative feedback loops, intermediary lipid metabolites-mediated allosteric regulation and dynamic protein-protein interactions. As aberrant adipocyte lipolysis is involved in various metabolic diseases and releasing the brakes on lipolysis in thermogenic adipocytes may activate thermogenesis, targeting adipocyte lipolysis is thus of therapeutic interest.

Keywords: adipocytes; feedback mechanisms; free fatty acid; lipolysis; lipophagy; molecular brakes; reesterification; thermogenesis

DOI: https://doi.org/10.3389/fphys.2022.826314

Proc Natl Acad Sci U S A. 2022 Mar 22. 119(12): e2114739119

Triglyceride breakdown from lipid droplets regulates the inflammatory response in macrophages.

Xanthe A M H van Dierendonck, Frank Vrieling, Lisa Smeehuijzen, Lei Deng, Joline P Boogaard, Cresci-Anne Croes, Lieve Temmerman, Suzan Wetzels, Erik Biessen, Sander Kersten, Rinke Stienstra.

SignificanceLipid droplets (LDs) are ubiquitous organelles that play important roles in cellular energy homeostasis, tightly regulating the accumulation and release of lipids. In macrophages, lipids accumulate in LDs during inflammation. However, it is unclear how inflammatory activation promotes the accumulation of lipids in LDs, and how the dynamic between lipid accumulation and breakdown could drive or inhibit inflammation. Elucidating the role of lipid accumulation during inflammation may provide important knowledge to influence inflammatory processes during health and disease. We identify the importance of the hypoxia-inducible lipid droplet-associated protein and the intracellular adipose triglyceride lipase in the regulation of lipid accumulation and breakdown in inflammatory macrophages. Furthermore, we determine the regulatory effect of lipid breakdown from LDs in supporting inflammation.

Keywords: ATGL; HILPDA; immunometabolism; lipid droplets; macrophages

DOI: https://doi.org/10.1073/pnas.2114739119

Adipocyte. 2022 Dec;11(1): 164-174

An organoid model derived from human adipose stem/progenitor cells to study adipose tissue physiology.

Markus Mandl, Hans P Viertler, Florian M Hatzmann, Camille Brucker, Sonja Großmann, Petra Waldegger, Tina Rauchenwald, Monika Mattesich, Marit Zwierzina, Gerhard Pierer, Werner Zwerschke.

We established a functional adipose organoid model system for human adipose stem/progenitor cells (ASCs) isolated from white adipose tissue (WAT). ASCs were forced to self-aggregate by a hanging-drop technique. Afterwards, spheroids were transferred into agar-coated cell culture dishes to avoid plastic-adherence and dis-aggregation. Adipocyte differentiation was induced by an adipogenic hormone cocktail. Morphometric analysis revealed a significant increase in organoid size in the course of adipogenesis until d 18. Whole mount staining of organoids using specific lipophilic dyes showed large multi- and unilocular fat deposits in differentiated cells indicating highly efficient differentiation of ASCs into mature adipocytes. Moreover, we found a strong induction of the expression of key adipogenesis and adipocyte markers (CCAAT/enhancer-binding protein (C/EBP) β, peroxisome proliferator-activated receptor (PPAR) γ, fatty acid-binding protein 4 (FABP4), adiponectin) during adipose organoid formation. Secreted adiponectin was detected in the cell culture supernatant, underscoring the physiological relevance of mature adipocytes in the organoid model. Moreover, colony formation assays of collagenase-digested organoids revealed the maintenance of a significant fraction of ASCs within newly formed organoids. In conclusion, we provide a reliable and highly efficient WAT organoid model, which enables accurate analysis of cellular and molecular markers of adipogenic differentiation and adipocyte physiology.

Keywords: Adipogenesis; adipocyte; adipose tissue; ageing; obesity; organoid; regenerative medicine; spheroid; stem cells

DOI: https://doi.org/10.1080/21623945.2022.2044601