Exercise training remodels inguinal white adipose tissue through adaptations in innervation, vascularization, and the extracellular matrix

Pasquale Nigro; Maria Vamvini; Jiekun Yang; Tiziana Caputo; Li-Lun Ho; Nicholas P Carbone; Danae Papadopoulos; Royce Conlin; Jie He; Michael F Hirshman; Joseph D White; Jacques Robidoux; Robert C Hickner; Søren Nielsen; Bente K Pedersen; Manolis Kellis; Roeland J W Middelbeek; Laurie J Goodyear

doi:10.1016/j.celrep.2023.112392

Exercise training remodels inguinal white adipose tissue through adaptations in innervation, vascularization, and the extracellular matrix

Cell Rep. 2023 Apr 25;42(4):112392. doi: 10.1016/j.celrep.2023.112392. Epub 2023 Apr 13.

Authors

Pasquale Nigro¹, Maria Vamvini², Jiekun Yang³, Tiziana Caputo⁴, Li-Lun Ho³, Nicholas P Carbone¹, Danae Papadopoulos³, Royce Conlin¹, Jie He¹, Michael F Hirshman¹, Joseph D White⁵, Jacques Robidoux⁵, Robert C Hickner⁶, Søren Nielsen⁷, Bente K Pedersen⁷, Manolis Kellis³, Roeland J W Middelbeek², Laurie J Goodyear⁸

Affiliations

¹ Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA.
² Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA; Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
³ Computational Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁴ Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA; Computational Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁵ Department of Pharmacology and Toxicology, East Carolina University, Greenville, NC, USA.
⁶ Department of Pharmacology and Toxicology, East Carolina University, Greenville, NC, USA; Department of Nutrition and Integrative Physiology, Florida State University, Tallahassee, FL, USA.
⁷ The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
⁸ Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA. Electronic address: laurie.goodyear@joslin.harvard.edu.

Abstract

Inguinal white adipose tissue (iWAT) is essential for the beneficial effects of exercise training on metabolic health. The underlying mechanisms for these effects are not fully understood, and here, we test the hypothesis that exercise training results in a more favorable iWAT structural phenotype. Using biochemical, imaging, and multi-omics analyses, we find that 11 days of wheel running in male mice causes profound iWAT remodeling including decreased extracellular matrix (ECM) deposition and increased vascularization and innervation. We identify adipose stem cells as one of the main contributors to training-induced ECM remodeling, show that the PRDM16 transcriptional complex is necessary for iWAT remodeling and beiging, and discover neuronal growth regulator 1 (NEGR1) as a link between PRDM16 and neuritogenesis. Moreover, we find that training causes a shift from hypertrophic to insulin-sensitive adipocyte subpopulations. Exercise training leads to remarkable adaptations to iWAT structure and cell-type composition that can confer beneficial changes in tissue metabolism.

Keywords: Adipo-Clear; CP: Metabolism; CP: Molecular biology; ECM; NEGR1; PRDM16; exercise; innervation; proteomics; spatial transcriptomics; vascularization; white adipose tissue.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Acclimatization / physiology
Adaptation, Physiological / physiology
Adipose Tissue / metabolism
Adipose Tissue, Brown / metabolism
Adipose Tissue, White* / metabolism
Animals
Cell Adhesion Molecules, Neuronal / metabolism
Male
Mice
Mice, Inbred C57BL
Motor Activity*
Transcription Factors / metabolism

Substances

Transcription Factors
NEGR1 protein, mouse
Cell Adhesion Molecules, Neuronal

Abstract

Publication types

MeSH terms

Substances

Grants and funding