A PRDM16-Driven Metabolic Signal from Adipocytes Regulates Precursor Cell Fate

Abstract

The precursor cells for metabolically beneficial beige adipocytes can alternatively become fibrogenic and contribute to adipose fibrosis. We found that cold exposure or b3-adrenergic agonist treatment of mice decreased the fibrogenic profile of precursor cells and stimulated beige adipocyte differentiation. This fibrogenic-to-adipogenic transition was impaired in aged animals, correlating with reduced adipocyte expression of the transcription factor PRDM16. Genetic loss of Prdm16 mimicked the effect of aging in promoting fibrosis, whereas increasing PRDM16 in aged mice decreased fibrosis and restored beige adipose development. PRDM16expressing adipose cells secreted the metabolite b-hydroxybutyrate (BHB), which blocked precursor fibrogenesis and facilitated beige adipogenesis. BHB catabolism in precursor cells, mediated by BDH1, was required for beige fat differentiation in vivo. Finally, dietary BHB supplementation in aged animals reduced adipose fibrosis and promoted beige fat formation. Together, our results demonstrate that adipocytes secrete a metabolite signal that controls beige fat remodeling. * * Figure 1. Cold or b3 Agonism Induces a Fibrogenic-to-Adipogenic Phenotypic Shift in Adipose Stromal Cells (A-E) Young (2-month-old) and aged (12-month-old) mice were acclimated to thermoneutrality and treated with vehicle or CL for 4 days to induce beiging. (A) Immunofluorescence staining for UCP1 (green) in iWAT. Nuclei (DAPI, blue); scale bar, 1 mm.

MicroRNA‐130a controls bone marrow mesenchymal stem cell differentiation towards the osteoblastic and adipogenic fate

“…It is believed that Runx2 is a specific osteoblast transcription factor, which plays essential roles in bone formation . agomiR‐130a up‐regulated Runx2 expression while antagomiR‐130a down‐regulated it (Figure C).…”

“…MiRNAs combined with target mRNA on sites of the 3′‐UTR to regulate the expression of target mRNA in post‐transcriptional manner. It is well known that Smurf2 can suppress the expression of Runx2 activity, a critical osteoblast‐specific transcription factor, which leads to decreasing in osteoblast formation . Several studies have clearly demonstrated that PPARγ is highly expressed in early stage of adipogenesis and plays a key role in adipocyte formation .…”

“…42 a critical osteoblast-specific transcription factor, which leads to decreasing in osteoblast formation. 39,40 Several studies have clearly demonstrated that PPARγ is highly expressed in early stage of adipogenesis and plays a key role in adipocyte formation. 44,45 We illustrated that miR-130a promotes osteogenesis of BMSC by eliminating the effect of Smurf2 and acts as a negative regulator of adipogenesis of BMSC by directly targeting PPARγ.…”

“…PPARγ, important regulator of adipocyte differentiation and metabolism, is required for adipogenesis, insulin sensitivity regulation and adipocyte survival and function. 40,41 By sequence analysis, MiR-130a had potential binding sites in the 3'UTR of PPARγ both in humans and rat ( Figure 6A). Luciferase report vectors were generated with wild type and mutated PPARγ 3'UTR (WT-pGL3-PPARγ and MUT-pGL3-PPARγ).…”

Trpm8 modulates thermogenesis in a sex-dependent manner without influencing cold-induced bone loss

“…Subcutaneous WAT is more susceptible to acquiring beige adipose features compared to other WAT depots, due to its high sympathetic innervation and norepinephrine turnover rate [5]. While these functions are preserved in infants, aging leads to decreased SNS activity [6], muscle mass [7], and brown adipose mass [8] as well as impaired fatty acid oxidation, glucose tolerance, and mitochondrial biogenesis [9], leading to reduced basal metabolism, energy expenditure and impaired thermoregulatory capacity.…”