Dpp4+ interstitial progenitor cells contribute to basal and high fat diet-induced adipogenesis

Megan Stefkovich; Sarah Traynor; Lan Cheng; David Merrick; Patrick Seale

doi:10.1016/j.molmet.2021.101357

Dpp4+ interstitial progenitor cells contribute to basal and high fat diet-induced adipogenesis

Mol Metab. 2021 Dec:54:101357. doi: 10.1016/j.molmet.2021.101357. Epub 2021 Oct 15.

Authors

Megan Stefkovich¹, Sarah Traynor², Lan Cheng³, David Merrick⁴, Patrick Seale⁵

Affiliations

¹ Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, Division of Endocrinology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: mstefko@pennmedicine.upenn.edu.
² Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, Division of Endocrinology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: sarah.traynor@pennmedicine.upenn.edu.
³ Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: lancheng@pennmedicine.upenn.edu.
⁴ Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, Division of Endocrinology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: david.merrick@pennmedicine.upenn.edu.
⁵ Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: sealep@pennmedicine.upenn.edu.

Abstract

Objective: The capacity to generate new adipocytes from precursor cells is critical for maintaining metabolic health. Adipocyte precursor cells (APCs) constitute a heterogenous collection of cell types; however, the contribution of these various cell types to adipose tissue expansion in vivo remains unknown. The aim of the current study is to investigate the contribution of Dpp4+ progenitors to de novo adipogenesis.

Methods: Single cell analysis has identified several transcriptionally distinct subpopulations of APCs, including Dpp4+ progenitor cells concentrated in the connective tissue surrounding many organs, including white adipose tissue (WAT). Here, we generated a Dpp4^CreER mouse model for in vivo lineage tracing of these cells and their downstream progeny in the setting of basal or high fat diet (HFD)-stimulated adipogenesis.

Results: Dpp4^CreER mice enabled specific temporal labeling of Dpp4+ progenitor cells within their native connective tissue niche. Following a dietary chase period consisting of chow or HFD feeding for 18 weeks, Dpp4+ progenitors differentiated into mature adipocytes within the gonadal and subcutaneous WAT. HFD stimulated adipogenic contribution from Dpp4+ cells in the gonadal but not the subcutaneous depot. Flow cytometry analysis revealed that Dpp4+ progenitors give rise to DPP4(-)/ICAM1+ preadipocytes in vivo. HFD feeding did not perturb the flux of Dpp4+ cell conversion into ICAM1+ preadipocytes in gonadal WAT. Conversely, in subcutaneous WAT, HFD feeding/obesity led to an accumulation of ICAM1+ preadipocytes without a corresponding increase in mature adipocyte differentiation. Examination of non-classical murine visceral depots with relevance to humans, including omentum and retroperitoneal WAT, revealed robust contribution of Dpp4+ progenitors to de novo adipogenesis, which was further stimulated by HFD.

Conclusion: Our data demonstrate that Dpp4+ interstitial progenitor cells contribute to basal adipogenesis in all fat depots and are recruited to support de novo adipogenic expansion of visceral WAT in the setting of HFD-induced obesity.

Keywords: Adipose tissue; DPP4; ICAM1; Mesenchymal stem cell; Obesity; Preadipocyte.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Adipogenesis / drug effects*
Animals
Diet, High-Fat / adverse effects*
Dipeptidyl Peptidase 4 / metabolism*
Intestines / metabolism*
Mice
Mice, Inbred Strains
Stem Cells / metabolism*

Substances

Dipeptidyl Peptidase 4
Dpp4 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding