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Perivascular adipocyte progenitor cells (APCs) can generate cold temperature-induced thermogenic beige adipocytes within white adipose tissue (WAT), an effect that could counteract excess fat mass and metabolic pathologies. Yet, the ability to generate beige adipocytes declines with age, creating a key challenge for their therapeutic potential. Here we show that ageing beige APCs overexpress platelet derived growth factor receptor beta ( Pdgfrβ ) to prevent beige adipogenesis. We show that genetically deleting Pdgfrβ , in adult male mice, restores beige adipocyte generation whereas activating Pdgfrβ in juvenile mice blocks beige fat formation. Mechanistically, we find that Stat1 phosphorylation mediates Pdgfrβ beige APC signaling to suppress IL-33 induction, which dampens immunological genes such as IL-13 and IL-5 . Moreover, pharmacologically targeting Pdgfrβ signaling restores beige adipocyte development by rejuvenating the immunological niche. Thus, targeting Pdgfrβ signaling could be a strategy to restore WAT immune cell function to stimulate beige fat in adult mammals. Thermogenic beige fat can reduce fat mass and improve metabolic health, yet the ability to form beige fat rapidly declines with age. Here, the authors show that targeting the age-related ramping of Pdgfrβ signalling restores the ageing adipose tissue niche to ignite beige fat development.

Sex steroids modulate the distribution of mammalian white adipose tissues. Moreover, WAT remodeling requires adipocyte progenitor cells. Nevertheless, the sex-dependent mechanisms regulating adipocyte progenitors remain undetermined. Here, we uncover Cxcr4 acting in a sexually dimorphic manner to affect a pool of proliferating cells leading to restriction of female fat mass. We find that deletion of Cxcr4 in Pparγ -expressing cells results in female, not male, lipodystrophy, which cannot be restored by high-fat diet consumption. Additionally, Cxcr4 deletion is associated with a loss of a pool of proliferating adipocyte progenitors. Cxcr4 loss is accompanied by the upregulation of estrogen receptor alpha in adipose-derived PPARγ-labelled cells related to estradiol hypersensitivity and stalled adipogenesis. Estrogen removal or administration of antiestrogens restores WAT accumulation and dynamics of adipose-derived cells in Cxcr4 -deficient mice. These findings implicate Cxcr4 as a female adipogenic rheostat, which may inform strategies to target female adiposity. Sex steroid receptor activity controls the distribution and growth of adipose tissues. Here, the authors reveal that Cxcr4 regulates the Pparg-marked adipose lineage to restrict female fat mass by modifying estrogen receptor expression and activity.

Beige adipocytes are induced by cold temperatures or β3-adrenergic receptor (Adrb3) agonists. They create heat through glucose and fatty acid (FA) oxidation, conferring metabolic benefits. The distinct and shared mechanisms by which these treatments induce beiging are unknown. Here, we perform single-nucleus assay for transposase-accessible chromatin sequencing (snATAC-seq) on adipose tissue from mice exposed to cold or an Adrb3 agonist to identify cellular and chromatin accessibility dynamics during beiging. Both stimuli induce chromatin remodeling that influence vascularization and inflammation in adipose. Beige adipocytes from cold-exposed mice have increased accessibility at genes regulating glycolytic processes, whereas Adrb3 activation increases cAMP responses. While both thermogenic stimuli increase accessibility at genes regulating thermogenesis, lipogenesis, and beige adipocyte development, the kinetics and magnitudes of the changes are distinct for the stimuli. Accessibility changes at lipogenic genes are linked to functional changes in lipid composition of adipose. Both stimuli tend to decrease the proportion of palmitic acids, a saturated FA in adipose. However, Adrb3 activation increases the proportion of monounsaturated FAs, whereas cold increases the proportion of polyunsaturated FAs. These findings reveal common and distinct mechanisms of cold and Adrb3 induced beige adipocyte biogenesis, and identify unique functional consequences of manipulating these pathways in vivo. Adipocyte beiging is a thermogenic response to cold exposure and b3-adrenergic receptor agonists, which exert their effects by distinct and common molecular mechanisms that control chromatin accessibility and lipid metabolism.

Platelet Derived Growth Factor Receptor Beta (Pdgfrβ) suppresses the formation of cold temperature-induced beige adipocytes in aged mammals. We aimed to determine if deleting Pdgfrβ in aged mice could rejuvenate metabolically active beige adipocytes by activating group 2 innate lymphoid cells (ILC2), and whether this effect could counteract diet-induced obesity-associated beige fat decline. We employed Pdgfrβ gain-of-function and loss-of-function mouse models targeting beige adipocyte progenitor cells (APCs). Our approach included cold exposure, metabolic cage analysis, and age and diet-induced obesity models to examine beige fat development and metabolic function under varied Pdgfrβ activity. Acute cold exposure alone enhanced metabolic benefits in aged mice, irrespective of beige fat generation. However, Pdgfrβ deletion in aged mice reestablished the formation of metabolically functional beige adipocytes, enhancing metabolism. Conversely, constitutive Pdgfrβ activation in young mice stymied beige fat development. Mechanistically, Pdgfrβ deletion upregulated IL-33, promoting ILC2 recruitment and activation, whereas Pdgfrβ activation reduced IL-33 levels and suppressed ILC2 activity. Notably, diet-induced obesity markedly increased Pdgfrβ expression and Stat1 signaling, which inhibited IL-33 induction and ILC2 activation. Genetic deletion of Pdgfrβ restored beige fat formation in obese mice, improving whole-body metabolism. This study reveals that cold temperature exposure alone can trigger metabolic activation in aged mammals. However, reversing Pdgfrβ signaling in aged and obese mice not only restores beige fat formation but also renews metabolic function and enhances the immunological environment of white adipose tissue (WAT). These findings highlight Pdgfrβ as a crucial target for therapeutic strategies aimed at combating age- and obesity-related metabolic decline.

In just the past few decades, the prevalence of obesity has nearly tripled worldwide, with the main driver of this growing epidemic being an imbalance in energy metabolism. Here, energy in dominates energy out resulting in the pathological expansion and remodeling of one’s white adipose tissue (WAT). This is often accompanied by metabolic diseases such as type 2 diabetes, cardiovascular disease, and ectopic fat accumulation. Contrary to energy storing WAT, mammals also contain thermogenic fat cells- brown and beige adipocytes. Thermogenic fat possesses the unique ability to utilize substrates such as glucose and fatty acids to produce heat. Therefore, the generation of thermogenic fat has great clinical utility in targeting metabolically unhealthy WAT. However, thermogenic fat presence as well as function declines with both age and obesity. Thus, understanding the molecular pathways and mechanisms that regulate both white and thermogenic fat development and function is critical for the generation of therapies to thwart obesity and metabolic syndrome. Here, we identify platelet derived growth factor-b (PDGFRb) signaling as a regulator of both WAT and beige fat development. PDGFRb is a membrane bound receptor tyrosine kinase involved in numerous signal transduction pathways. We have found that deleting PDGFRb in white adipocyte progenitor cells (APCs) impairs adult WAT homeostasis, resulting in lipodystrophy, fibrotic tissue accumulation and immune cell infiltration. Mechanistically, PDGFRb is essential in specification of the adult white APC lineage, with embryonic deletion of PDGFRb in adult white APCs resulting in a lineage switch. PDGFRb deficient APCs instead develop into macrophages, not white adipocytes, impairing adult WAT function. In contrast to white fat development, we have additionally uncovered the role of PDGFRb in cold induced beige fat development. Here, we find that PDGFRb expression increases in beige APCs throughout the aging process to negatively regulate beige fat formation via downstream Stat1 phosphorylation. Deleting PDGFRb in aged beige APCs restores beige fat generation in response to cold temperature challenge. Interestingly however, loss of PDGFRb in aged beige APCs does not restore their ability to undergo beige adipogenesis. Instead, we find that with aging, the immune cell composition within the adipose tissue niche is disrupted, hindering beige fat formation. Targeting the PDGFRbStat1 pathway, either genetically or pharmacologically, restores the presence and activation of these immune cells to promote beiging and improve whole body metabolism. Overall, these studies highlight the PDGFRb signaling pathway as a promising potential target in combatting the current obesity epidemic.

Muscle cell fusion is critical for forming and maintaining multinucleated myotubes during skeletal muscle development and regeneration. However, the molecular mechanisms directing cell-cell fusion are not fully understood. Here, we identify platelet-derived growth factor receptor beta (PDGFRβ) signaling as a key modulator of myocyte fusion in adult muscle cells. Our findings demonstrate that genetic deletion of enhances muscle regeneration and increases myofiber size, whereas PDGFRβ activation impairs muscle repair. Inhibition of PDGFRβ activity promotes myonuclear accretion in both mouse and human myotubes, whereas PDGFRβ activation stalls myotube development by preventing cell spreading to limit fusion potential. Transcriptomics analysis show that PDGFRβ signaling cooperates with TGFβ signaling to direct myocyte size and fusion. Mechanistically, PDGFRβ signaling requires STAT1 activation, and blocking STAT1 phosphorylation enhances myofiber repair and size during regeneration. Collectively, PDGFRβ signaling acts as a regenerative checkpoint and represents a potential clinical target to rapidly boost skeletal muscle repair.

Beige adipocytes are induced by cold temperatures or β3-adrenergic receptor (Adrb3) agonists. They create heat through glucose and fatty acid (FA) oxidation, conferring metabolic benefits. The distinct and shared mechanisms by which these treatments induce beiging are unknown. Here, we performed single-nucleus assay for transposase-accessible chromatin sequencing (snATAC-seq) on adipose tissue from mice exposed to cold or an Adrb3 agonist to identify cellular and chromatin accessibility dynamics during beiging. Both stimuli induce chromatin remodeling that influence vascularization and inflammation in adipose. Beige adipocytes from cold-exposed mice have increased accessibility at genes regulating glycolytic processes, whereas Adrb3 activation increases cAMP responses. While both thermogenic stimuli increase accessibility at genes regulating thermogenesis, lipogenesis, and beige adipocyte development, the kinetics and magnitudes of the changes are distinct for the two stimuli. Accessibility changes at lipogenic genes are linked to functional changes in lipid composition of adipose. Both stimuli tend to decrease the proportion of palmitic acids, a saturated FA in adipose. However, Adrb3 activation increases the proportion of monounsaturated FAs, whereas cold increases the proportion of polyunsaturated FAs. These findings reveal common and distinct mechanisms of cold and Adrb3 induced beige adipocyte biogenesis, and identify the unique functional consequences of manipulating these pathways in vivo. Competing Interest Statement The authors have declared no competing interest.