Aging impairs cold-induced beige adipogenesis and adipocyte metabolic reprogramming

Abstract

The energy-burning capability of beige adipose tissue is a potential therapeutic tool for reducing obesity and metabolic disease, but this capacity is decreased by aging. Here, we evaluate the impact of aging on the profile and activity of adipocyte stem and progenitor cells (ASPCs) and adipocytes during the beiging process. We found that aging increases the expression of Cd9 and other fibrogenic genes in fibroblastic ASPCs and blocks their differentiation into beige adipocytes. Fibroblastic ASPC populations from young and aged mice were equally competent for beige differentiation in vitro, suggesting that environmental factors suppress adipogenesis in vivo. Examination of adipocytes by single nucleus RNA-sequencing identified compositional and transcriptional differences in adipocyte populations with age and cold exposure. Notably, cold exposure induced an adipocyte population expressing high levels of de novo lipogenesis (DNL) genes, and this response was severely blunted in aged animals. We further identified natriuretic peptide clearance receptor Npr3, a beige fat repressor, as a marker gene for a subset of white adipocytes and an aging-upregulated gene in adipocytes. In summary, this study indicates that aging blocks beige adipogenesis and dysregulates adipocyte responses to cold exposure and provides a unique resource for identifying cold and/or aging-regulated pathways in adipose tissue.

A distinct subpopulation of adipocytes in adult perirenal adipose tissue arises through brown-to-white conversion but reverts to a thermogenic phenotype upon cold exposure

“…Surprisingly, a second adipocyte subpopulation that was almost specific to cold exposed animals (iWAT-ad2) did not express any of the common thermogenic markers, but instead specifically expressed genes involved in lipogenesis (Acss2, Fasn and Acly) (Figure S6G-H). This is in agreement with a recent study showing that expression of lipogenic genes is highly induced in iWAT adipocytes upon cold exposure (Holman et al, 2023). In contrast to iWAT-ad1 and ad2, the abundance of iWAT-ad4 cells decreased by half following cold exposure (Figure S6G).…”

Mesenchymal stromal cells as conductors of adipose tissue remodeling

“…5 ; Wang et al 2019 ). Seale and colleagues ( Wang et al 2019 ; Holman et al 2023 ) demonstrated that the loss of this metabolite signaling to adipocyte precursors, rather than an intrinsic defect in the adipogenic activity of the cells, may contribute to the age-related decline in the capacity for thermogenic WAT remodeling. Independently, Abe et al (2022) revealed that the proliferation of CD81 + preadipocytes is stimulated by the linoleic acid released from mature adipocytes during the process of lipolysis ( Fig.…”