PPARγ Transcription Deficiency Exacerbates High-Fat Diet-Induced Adipocyte Hypertrophy and Insulin Resistance in Mice

Abstract

Background: The transcriptional factor peroxisome proliferator-activated receptor g (PPARg) is an important therapeutic target for the treatment of type 2 diabetes. However, the role of the PPARg transcriptional activity remains ambiguous in its metabolic regulation. Methods: Based on the crystal structure of PPARg bound with the DNA target of PPARg response element (PPRE), Arg134, Arg135, and Arg138, three crucial DNA binding sites for PPARg, were mutated to alanine (3RA), respectively. In vitro AlphaScreen assay and cell-based reporter assay validated that PPARg 3RA mutant cannot bind with PPRE and lost transcriptional activity, while can still bind ligand (rosiglitazone) and cofactors (SRC1, SRC2, and NCoR). By using CRISPR/Cas9, we created mice that were heterozygous for PPARg-3RA (PPARg 3RA/+). The phenotypes of chow diet and high-fat diet fed PPARg 3RA/+ mice were investigated, and the molecular mechanism were analyzed by assessing the PPARg transcriptional activity. Results: Homozygous PPARg-3RA mutant mice are embryonically lethal. The mRNA levels of PPARg target genes were significantly decreased in PPARg 3RA/+ mice. PPARg 3RA/+ mice showed more severe adipocyte hypertrophy, insulin resistance, and hepatic steatosis than wild type mice when fed with high-fat diet. These phenotypes were ameliorated after the transcription activity of PPARg was restored by rosiglitazone, a PPARg agonist. Conclusion: The current report presents a novel mouse model for investigating the role of PPARg transcription in physiological functions. The data demonstrate that the transcriptional activity plays an indispensable role for PPARg in metabolic regulation.

Stimulator of interferon genes promotes diabetic sarcopenia by targeting peroxisome proliferator activated receptors γ degradation and inhibiting fatty acid oxidation

“…In addition to mitofission and mitophagy, PPARγ‐mediated FAO also influences IR. As reported, PPARγ inhibition promoted the development of IR in response to metabolic stress 39 . Promoting FAO by overexpressing CPT1 alleviated IR in skeletal muscles under HFD conditions, 40 whereas inhibiting FAO by knocking out CPT2 potentiated PA‐induced IR in C2C12 myotubes 41 .…”

“…As reported, PPARγ inhibition promoted the development of IR in response to metabolic stress. 39 Promoting FAO by overexpressing CPT1 alleviated IR in skeletal muscles under HFD conditions, 40 whereas inhibiting FAO by knocking out CPT2 potentiated PA‐induced IR in C2C12 myotubes. 41 Although transient inhibition of mitochondrial FAO can increase glucose utilization by peripheral tissue and reduce fasting blood glucose, long‐term FAO impairment can lead to systemic IR.…”

Hypertrophy and ER Stress Induced by Palmitate Are Counteracted by Mango Peel and Seed Extracts in 3T3-L1 Adipocytes

“…The ability of MPE and MSE to reduce lipid content in PA-treated adipocytes results from both stimulation of lipolysis and inhibition of lipogenesis. PPARγ is a transcription factor that has been reported to play a critical role in adipocyte hypertrophy under high fat diets [ 60 ]. We provided evidence that the PPARγ level increased under PA-treatment in differentiated 3T3-L1 adipocytes.…”

Circ003429 Regulates Unsaturated Fatty Acid Synthesis in the Dairy Goat Mammary Gland by Interacting with miR-199a-3p, Targeting the YAP1 Gene

“…PPARγ is a member of the nuclear hormone receptor superfamily that functions as a key transcription factor during adipogenesis. Overexpression of PPARγ also significantly upregulates the PPAR response element (PPRE) [ 29 ], which regulates the transcriptional activity of Stearoyl-Coenzyme A Desaturase 1 ( SCD1 ) by directly binding to this element [ 30 ]. Overexpression of PPARγ in GEMCs results in upregulated SCD1 expression, decreased contents of c16:0 and c18:0, and increased contents of c16:1 and C18:1 [ 31 ].…”