Aging-dependent regulatory cells emerge in subcutaneous fat to inhibit adipogenesis

Nguyen, Hai P.; Lin, Frances; Yi, Danielle; Xie, Ying; Dinh, Jennie; Xue, Pengya; Sul, Hei Sook

doi:10.1016/j.devcel.2021.03.026

Cited by 77 publications

(69 citation statements)

References 87 publications

(111 reference statements)

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“…Caution needs to be used when employing CD142 as a marker to isolate P3 cells, as adipogenic CD142-expressing P2-2 cells will also be collected. This fact might explain the divergent findings regarding the adipogenic potential of P3 cells 4 , 9 , 23 . In our previous study 9 , we observed a continuum of CD142-expressing cells within the Lin − Sca1 + (enriched pool of APCs) cell fraction (Extended Data Fig.…”

Section: Resultsmentioning

confidence: 98%

Identification of a regulatory pathway inhibiting adipogenesis via RSPO2

et al. 2022

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Healthy adipose tissue remodeling depends on the balance between de novo adipogenesis from adipogenic progenitor cells and the hypertrophy of adipocytes. De novo adipogenesis has been shown to promote healthy adipose tissue expansion, which confers protection from obesity-associated insulin resistance. Here, we define the role and trajectory of different adipogenic precursor subpopulations and further delineate the mechanism and cellular trajectory of adipogenesis, using single-cell RNA-sequencing datasets of murine adipogenic precursors. We identify Rspo2 as a functional regulator of adipogenesis, which is secreted by a subset of CD142+ cells to inhibit maturation of early progenitors through the receptor Lgr4. Increased circulating RSPO2 in mice leads to adipose tissue hypertrophy and insulin resistance and increased RSPO2 levels in male obese individuals correlate with impaired glucose homeostasis. Taken together, these findings identify a complex cellular crosstalk that inhibits adipogenesis and impairs adipose tissue homeostasis.

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Section: Resultsmentioning

confidence: 98%

Identification of a regulatory pathway inhibiting adipogenesis via RSPO2

et al. 2022

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“…Recently, a novel subpopulation of cells named aging-dependent regulatory cells (ARCs) was identified through single-cell RNA-Seq analysis of subcutaneous adipose tissue ( 53 ). ARCs are proinflammatory and inhibit differentiation and proliferation of neighboring progenitor cells, but are distinct from senescent cells in that they can proliferate.…”

Section: Tissue-specific Changes In Structure and Function With Agingmentioning

confidence: 99%

“…It is not yet known whether they exist in visceral adipose tissue in humans. Nguyen et al ( 53 ) proposed that ARCs may be involved in the loss of subcutaneous adipose tissue with age by inhibiting adipogenesis.…”

Section: Tissue-specific Changes In Structure and Function With Agingmentioning

confidence: 99%

Metabolic changes in aging humans: current evidence and therapeutic strategies

Palmer¹,

Jensen²

2022

Journal of Clinical Investigation

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Aging and metabolism are inextricably linked, and many age-related changes in body composition, including increased central adiposity and sarcopenia, have underpinnings in fundamental aging processes. These age-related changes are further exacerbated by a sedentary lifestyle and can be in part prevented by maintenance of activity with aging. Here we explore the age-related changes seen in individual metabolic tissues — adipose, muscle, and liver — as well as globally in older adults. We also discuss the available evidence for therapeutic interventions such as caloric restriction, resistance training, and senolytic and senomorphic drugs to maintain healthy metabolism with aging, focusing on data from human studies.

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“…The underlying mechanism is not well characterized. A recent study identified a sub-population of adipocytes present only in the subcutaneous adipose tissue of older mice or humans ( Nguyen et al, 2021 ). These cells have elevated PU.1 expression, which causes defective adipogenesis and proinflammatory cytokines secretion to inhibit adipogenesis of neighboring cells.…”

Section: Discussionmentioning

confidence: 99%

Adipocyte-Specific Ablation of PU.1 Promotes Energy Expenditure and Ameliorates Metabolic Syndrome in Aging Mice

et al. 2022

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Objective: Although PU.1/Spi1 is known as a master regulator for macrophage development and function, we have reported previously that it is also expressed in adipocytes and is transcriptionally induced in obesity. Here, we investigated the role of adipocyte PU.1 in the development of the age-associated metabolic syndrome.Methods: We generated mice with adipocyte-specific PU.1 knockout, assessed metabolic changes in young and older adult PU.1fl/fl (control) and AdipoqCre PU.1fl/fl (aPU.1KO) mice, including body weight, body composition, energy expenditure, and glucose homeostasis. We also performed transcriptional analyses using RNA-Sequencing of adipocytes from these mice.Results: aPU.1KO mice have elevated energy expenditure at a young age and decreased adiposity and increased insulin sensitivity in later life. Corroborating these observations, transcriptional network analysis indicated the existence of validated, adipocyte PU.1-modulated regulatory hubs that direct inflammatory and thermogenic gene expression programs.Conclusion: Our data provide evidence for a previously uncharacterized role of PU.1 in the development of age-associated obesity and insulin resistance.

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Aging-dependent regulatory cells emerge in subcutaneous fat to inhibit adipogenesis

Cited by 77 publications

References 87 publications

Identification of a regulatory pathway inhibiting adipogenesis via RSPO2

Identification of a regulatory pathway inhibiting adipogenesis via RSPO2

Metabolic changes in aging humans: current evidence and therapeutic strategies

Adipocyte-Specific Ablation of PU.1 Promotes Energy Expenditure and Ameliorates Metabolic Syndrome in Aging Mice

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