High-fat diet-induced obesity regulates MMP3 to modulate depot- and sex-dependent adipose expansion in C57BL/6J mice

Yuanyuan Wu, Mi Jeong Lee, Yasuo Ido, Susan K. Fried

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

Increased adipocyte size is hypothesized to signal the recruitment of adipose progenitor cells (APCs) to expand tissue storage capacity. To investigate depot and sex differences in adipose growth, male and female C57BL/6J mice (10 wk-old) were challenged with high-fat (HF) or low-fat (LF) diets (D) for 14 wk. The HFD increased gonadal (GON) depot weight by adipocyte hypertrophy and hyperplasia in females but hypertrophy alone in males. In both sexes, inguinal (ING) adipocytes were smaller than GON, and depot expansion was due to hypertrophy. Matrix metalloproteinase 3 (Mmp3), an antiadipogenic factor, and its inhibitor Timps modulate the extracellular matrix remodeling needed for depot expansion. Mmp3 mRNA was depot different (ING > GON), higher in females than males and mainly expressed in APCs. In males, HFD-induced obesity increased tissue and APC Mmp3 mRNA levels and MMP3 protein and enzymatic activity. In females however, HFD significantly decreased MMP3 protein without affecting its mRNA levels. MMP3 activity also decreased (significant in ING). Timp4 mRNA was expressed mainly in adipocytes, and HFD-induced obesity tended to increase the ratio of TIMP4 to MMP3 protein in females, whereas it decreased it in males. Overexpression of Mmp3 in 3T3-L1 preadipocytes or rhMMP3 protein added to primary human preadipocytes inhibited differentiation, whereas rhTIMP4 improved adipogenesis and attenuated the inhibitory effect of rhMMP3. These data suggest that HFD-induced obesity downregulates APC MMP3 expression to trigger adipogenesis, and adipocyte TIMP4 may modulate this process to regulate hyperplastic vs. hypertrophic adipose tissue expansion, fat distribution, and metabolic health in a sex- and depot-dependent manner.

Original languageEnglish
Pages (from-to)E58-E71
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume312
Issue number1
DOIs
StatePublished - 1 Jan 2017
Externally publishedYes

Keywords

  • Adipocyte size
  • Adipose progenitor
  • Hyperplasia
  • Matrix metalloproteinase 3
  • Tissue inhibitor of matrix metalloproteinase 4

Fingerprint

Dive into the research topics of 'High-fat diet-induced obesity regulates MMP3 to modulate depot- and sex-dependent adipose expansion in C57BL/6J mice'. Together they form a unique fingerprint.

Cite this