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.
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.
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.
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.