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      Regulatory mechanisms of the early phase of white adipocyte differentiation: an overview

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          Abstract

          The adipose organ comprises two main fat depots termed white and brown adipose tissues. Adipogenesis is a process leading to newly differentiated adipocytes starting from precursor cells, which requires the contribution of many cellular activities at the genome, transcriptome, proteome, and metabolome levels. The adipogenic program is accomplished through two sequential phases; the first includes events favoring the commitment of adipose tissue stem cells/precursors to preadipocytes, while the second involves mechanisms that allow the achievement of full adipocyte differentiation. While there is a very large literature about the mechanisms involved in terminal adipogenesis, little is known about the first stage of this process. Growing interest in this field is due to the recent identification of adipose tissue precursors, which include a heterogenous cell population within different types of adipose tissue as well as within the same fat depot. In addition, the alteration of the heterogeneity of adipose tissue stem cells and of the mechanisms involved in their commitment have been linked to adipose tissue development defects and hence to the onset/progression of metabolic diseases, such as obesity. For this reason, the characterization of early adipogenic events is crucial to understand the etiology and the evolution of adipogenesis-related pathologies, and to explore the adipose tissue precursors’ potential as future tools for precision medicine.

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          Adipogenesis and metabolic health

          Obesity is characterized by increased adipose tissue mass and has been associated with a strong predisposition towards metabolic diseases and cancer. Thus, it constitutes a public health issue of major proportion. The expansion of adipose depots can be driven either by the increase in adipocyte size (hypertrophy) or by the formation of new adipocytes from precursor differentiation in the process of adipogenesis (hyperplasia). Notably, adipocyte expansion through adipogenesis can offset the negative metabolic effects of obesity, and the mechanisms and regulators of this adaptive process are now emerging. Over the past several years, we have learned a considerable amount about how adipocyte fate is determined and how adipogenesis is regulated by signalling and systemic factors. We have also gained appreciation that the adipogenic niche can influence tissue adipogenic capability. Approaches aimed at increasing adipogenesis over adipocyte hypertrophy can now be explored as a means to treat metabolic diseases.
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            Adipose Tissue Dysfunction as Determinant of Obesity-Associated Metabolic Complications

            Obesity is a critical risk factor for the development of type 2 diabetes (T2D), and its prevalence is rising worldwide. White adipose tissue (WAT) has a crucial role in regulating systemic energy homeostasis. Adipose tissue expands by a combination of an increase in adipocyte size (hypertrophy) and number (hyperplasia). The recruitment and differentiation of adipose precursor cells in the subcutaneous adipose tissue (SAT), rather than merely inflating the cells, would be protective from the obesity-associated metabolic complications. In metabolically unhealthy obesity, the storage capacity of SAT, the largest WAT depot, is limited, and further caloric overload leads to the fat accumulation in ectopic tissues (e.g., liver, skeletal muscle, and heart) and in the visceral adipose depots, an event commonly defined as “lipotoxicity.” Excessive ectopic lipid accumulation leads to local inflammation and insulin resistance (IR). Indeed, overnutrition triggers uncontrolled inflammatory responses in WAT, leading to chronic low-grade inflammation, therefore fostering the progression of IR. This review summarizes the current knowledge on WAT dysfunction in obesity and its associated metabolic abnormalities, such as IR. A better understanding of the mechanisms regulating adipose tissue expansion in obesity is required for the development of future therapeutic approaches in obesity-associated metabolic complications.
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              Adipose Tissue Distribution, Inflammation and Its Metabolic Consequences, Including Diabetes and Cardiovascular Disease

              Adipose tissue plays essential roles in maintaining lipid and glucose homeostasis. To date several types of adipose tissue have been identified, namely white, brown, and beige, that reside in various specific anatomical locations throughout the body. The cellular composition, secretome, and location of these adipose depots define their function in health and metabolic disease. In obesity, adipose tissue becomes dysfunctional, promoting a pro-inflammatory, hyperlipidemic and insulin resistant environment that contributes to type 2 diabetes mellitus (T2DM). Concurrently, similar features that result from adipose tissue dysfunction also promote cardiovascular disease (CVD) by mechanisms that can be augmented by T2DM. The mechanisms by which dysfunctional adipose tissue simultaneously promote T2DM and CVD, focusing on adipose tissue depot-specific adipokines, inflammatory profiles, and metabolism, will be the focus of this review. The impact that various T2DM and CVD treatment strategies have on adipose tissue function and body weight also will be discussed.
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                Author and article information

                Contributors
                emma.defabiani@unimi.it
                nico.mitro@unimi.it
                Journal
                Cell Mol Life Sci
                Cell Mol Life Sci
                Cellular and Molecular Life Sciences
                Springer International Publishing (Cham )
                1420-682X
                1420-9071
                20 February 2022
                20 February 2022
                2022
                : 79
                : 3
                : 139
                Affiliations
                GRID grid.4708.b, ISNI 0000 0004 1757 2822, DiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, , Università degli Studi di Milano, ; 20133 Milan, Italy
                Author information
                http://orcid.org/0000-0003-2791-4526
                http://orcid.org/0000-0001-6404-6321
                http://orcid.org/0000-0003-2115-778X
                http://orcid.org/0000-0001-9230-1078
                http://orcid.org/0000-0003-2406-1468
                http://orcid.org/0000-0002-5000-3619
                Article
                4169
                10.1007/s00018-022-04169-6
                8858922
                35184223
                083e5336-8c9b-4d03-9cfa-d5d12f13e9d9
                © The Author(s) 2022

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 27 October 2021
                : 10 January 2022
                : 24 January 2022
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100003407, Ministero dell’Istruzione, dell’Università e della Ricerca;
                Award ID: Progetto eccellenza 2018-2022
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001648, European Foundation for the Study of Diabetes;
                Award ID: MSD European Research Programme on New Targets for Type 2 Diabetes 2019
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100006781, Giovanni Armenise-Harvard Foundation;
                Award ID: Career development award
                Award Recipient :
                Categories
                Review
                Custom metadata
                © Springer Nature Switzerland AG 2022

                Molecular biology
                adipogenesis,obesity,transcriptional control of differentiation,epigenome modifications,cytoskeleton

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