Adipocytes: Becoming less beige with age

The production of beige adipocytes following cold exposure is blocked as mice get older and leads to changes in the expression of metabolic genes.
  1. Anying Song
  2. Qiong A Wang  Is a corresponding author
  1. Department of Molecular & Cellular Endocrinology, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Medical Center, United States
  2. Department of Molecular & Cellular Endocrinology, Arthur Riggs Diabetes and Metabolism Research Institute and the Comprehensive Cancer Center, Beckman Research Institute, City of Hope Medical Center, United States

Stored inside the fat deposits of humans and mice are thermogenic cells known as brown and beige adipocytes which burn energy and dissipate it as heat (Sakers et al., 2022). This allows the body to stay warm when temperatures drop and to maintain energy levels in response to physical activity. As individuals age, their ability to carry out this function – known as adaptive thermogenesis – declines, but it remains unclear why.

Unlike brown adipoctyes, which are located in brown adipose tissue (such as the fat deposit between shoulder blades), beige adipocytes are generated in white adipose tissue in response to certain stimuli, such as exposure to cold. The generation and activation of beige adipocytes, known as ‘beiging’, ameliorates high blood sugar (hyperglycemia) and lipid imbalances (dyslipidemia), and prevents obesity and disruption of the metabolism, making beige adipocytes a potential therapeutic target for metabolic diseases (Bartelt and Heeren, 2014; Min et al., 2016). However, beiging upon cold exposure declines with age in both rodents and humans (Berry et al., 2017; Wang et al., 2022; Benvie et al., 2023). Now, in eLife, Patrick Seale and colleagues – including Corey Holman as first author – report the results of experiments that shed light on the cellular mechanisms responsible for this age-related shift (Holman et al., 2023).

The team (who are based at the University of Pennsylvania, Beth Israel Deaconess Medical Center, Broad Institute of MIT and Harvard, and Harvard Medical School) induced beiging in the white adipose tissue in the inguinal region (also known as the groin) of mice by treating them with a drug that stimulates this process, or exposing them to cold. As expected, comparing young (9-week-old) and aged (57-week-old) mice showed that beiging was severely blunted and delayed as mice got older.

Beige adipocytes arise from adipose stem and progenitor cells via a procees known as de novo beige adipogenesis, or by reactivating dormant beige fat cells (Wang et al., 2013; Long et al., 2014; Wang et al., 2014; Vishvanath et al., 2016; Chen et al., 2019; Shao et al., 2019). Tracing the fate of adipocyte stem and progenitor cells – identified by their expression of the gene Pdgfra – in the white adipose tissue of reporter mice showed that aged mice produced much fewer beige adipocytes from these cells than their younger counterparts (Figure 1). This observation suggests that aging blocks de novo beige adipogenesis from adipocyte stem and progenitor cells.

How adipocytes change in young and aged mice following cold exposure.

Sitting in the white adipose tissue in the inguinal region (iWAT) of mice is a population of fat cells (represented by different coloured circles) and Pdgfra+ + stem and progenitor cells (ASPCs; top left panel). When mice are exposed to cold, ASPCs mature into beige adipocytes (yellow circles with yellow spots), which burn energy and generate heat (bottom left panel). Holman et al. found that this process, known as de novo beige adipogenesis, was blocked in older mice, resulting in less beige adipocytes being generated following cold exposure (bottom right panel). Further analysis revealed three other subpopulations of adipocytes in iWAT in addition to beige adipocytes: white adipocytes expressing high levels of the thermogenic gene Npr3 (red), and white adipocytes with low (DNL-low) or high (DNL-high) levels of de novo lipogenesis (represented as yellow and green respectively). Aging altered the proportion of DNL-low and DNL-high adipoctyes, and caused adipocytes to express higher levels of Npr3 (top panels). Cold exposure decreased the proportion DNL-low adipoctyes in both young and older mice. It also increased the expression of lipogenic genes involved in de novo lipogenesis in young mice (bottom left panel), but not middle-aged mice (bottom right panel).

Image credit: Figure created using BioRender.

To investigate which factors contribute to this age-related decline, Holman et al. analyzed the genes expressed in individual stem and progenitor cells which had been isolated from white adipose tissue in the inguinal region. This revealed that the adipocyte stem and progenitor cells did not change their cellular identity in response to aging or cold exposure. Further analysis revealed that aging increased the expression of fibrogenic genes, such as Cd9, and decreased Postn and other extracellular matrix-related genes in adipocyte stem and progenitor cells, which may affect beige adipogenesis during aging. Moreover, Holman et al. found that adipocyte stem and progenitor cells from young and aged mice were equally competent at maturing into beige adipocytes when cultured in vitro. These results suggest that external factors surrounding these stem cells or in the bloodstream must be contributing to the age-related decline in de novo beige adipogenesis rather than cell autonomous differences.

Finally, to determine how aging and cold exposure impacts gene expression in mature adipocytes, Holman et al. performed single nuclei RNA sequencing analyses of inguinal white adipose tissue. This identified beige adipocytes and three other types of ‘white’ fat cell: adipocytes which expressed high levels of a thermogenic gene called Npr3 that suppresses beige adipocytes from releasing energy, and adipocytes that display either high or low levels of de novo lipogenesis – the process of generating fat tissue – (named DNL-high and DNL-low, respectively; Figure 1). Aging affected the proportion of of all four adipocyte populations in white adipose tissue, and upregulated Npr3 in the three white adipocyte populations. Interestingly, de novo lipogenesis induced by cold exposure was severely impaired in the beige and DNL-high adipocytes of aged mice. These results suggest that the dysregulation of signaling pathways, such as Npr3 signaling and lipogenesis, during aging may contribute to declining beige adipogenesis.

Senescence of adipocyte progenitor cells (Berry et al., 2017; Benvie et al., 2023) and inactivation of thermogenic genes in mature fat cells (Wang et al., 2022) have already been associated with the age-related impairment of beiging. Here, Holman et al. provide direct in vivo evidence that de novo beige adipogenesis is also blocked during aging in mice, revealing another possible mechanism to explain age-related reductions in beige adipogenesis. This work also offers a unique resource for researchers who are trying to identify the signaling pathways related to reactivating dormant beige adipocytes.

References

Article and author information

Author details

  1. Anying Song

    Anying Song is in the Department of Molecular & Cellular Endocrinology, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Medical Center, Duarte, United States

    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0382-5238
  2. Qiong A Wang

    Qiong A Wang is in the Department of Molecular & Cellular Endocrinology, Arthur Riggs Diabetes and Metabolism Research Institute and the Comprehensive Cancer Center, Beckman Research Institute, City of Hope Medical Center, Duarte, United States

    For correspondence
    qwang@coh.org
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2224-4287

Publication history

  1. Version of Record published: July 7, 2023 (version 1)

Copyright

© 2023, Song and Wang

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 641
    Page views
  • 67
    Downloads
  • 0
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Anying Song
  2. Qiong A Wang
(2023)
Adipocytes: Becoming less beige with age
eLife 12:e89700.
https://doi.org/10.7554/eLife.89700
  1. Further reading

Further reading

    1. Cell Biology
    2. Plant Biology
    Maciek Adamowski, Ivana Matijević, Jiří Friml
    Research Article

    The GNOM (GN) Guanine nucleotide Exchange Factor for ARF small GTPases (ARF-GEF) is among the best studied trafficking regulators in plants, playing crucial and unique developmental roles in patterning and polarity. The current models place GN at the Golgi apparatus (GA), where it mediates secretion/recycling, and at the plasma membrane (PM) presumably contributing to clathrin-mediated endocytosis (CME). The mechanistic basis of the developmental function of GN, distinct from the other ARF-GEFs including its closest homologue GNOM-LIKE1 (GNL1), remains elusive. Insights from this study largely extend the current notions of GN function. We show that GN, but not GNL1, localizes to the cell periphery at long-lived structures distinct from clathrin-coated pits, while CME and secretion proceed normally in gn knockouts. The functional GN mutant variant GNfewerroots, absent from the GA, suggests that the cell periphery is the major site of GN action responsible for its developmental function. Following inhibition by Brefeldin A, GN, but not GNL1, relocates to the PM likely on exocytic vesicles, suggesting selective molecular associations en route to the cell periphery. A study of GN-GNL1 chimeric ARF-GEFs indicates that all GN domains contribute to the specific GN function in a partially redundant manner. Together, this study offers significant steps toward the elucidation of the mechanism underlying unique cellular and development functions of GNOM.

    1. Biochemistry and Chemical Biology
    2. Cell Biology
    Chenjie Xia, Huihui Xu ... Hongting Jin
    Research Article

    Glucocorticoid-induced osteonecrosis of the femoral head (GONFH) is a common refractory joint disease characterized by bone damage and the collapse of femoral head structure. However, the exact pathological mechanisms of GONFH remain unknown. Here, we observed abnormal osteogenesis and adipogenesis associated with decreased β-catenin in the necrotic femoral head of GONFH patients. In vivo and in vitro studies further revealed that glucocorticoid exposure disrupted osteogenic/adipogenic differentiation of bone marrow mesenchymal cells (BMSCs) by inhibiting β-catenin signaling in glucocorticoid-induced GONFH rats. Col2+ lineage largely contributes to BMSCs and was found an osteogenic commitment in the femoral head through 9 mo of lineage trace. Specific deletion of β-catenin gene (Ctnnb1) in Col2+ cells shifted their commitment from osteoblasts to adipocytes, leading to a full spectrum of disease phenotype of GONFH in adult mice. Overall, we uncover that β-catenin inhibition disrupting the homeostasis of osteogenic/adipogenic differentiation contributes to the development of GONFH and identify an ideal genetic-modified mouse model of GONFH.