The role of glutamine metabolism and ASCT2/SLC1A5 transporter on insulin resistance and endoplasmic reticulum stress in 3T3-L1 adipocytes

Aydogdu G., Sermikli B. P., ARAS E. S., YILMAZ E.

Cytotechnology, cilt.77, sa.5, 2025 (SCI-Expanded, Scopus) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 77 Sayı: 5
  • Basım Tarihi: 2025
  • Doi Numarası: 10.1007/s10616-025-00844-1
  • Dergi Adı: Cytotechnology
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, Biotechnology Research Abstracts, CAB Abstracts, EMBASE, Veterinary Science Database
  • Anahtar Kelimeler: ASCT2, Endoplasmic reticulum stress, Glutamine transporter, Insulin resistance, Obesity
  • Ankara Üniversitesi Adresli: Evet

Özet

Obesity is one of the major health issues of recent times. It is known that obesity increases endoplasmic reticulum (ER) stress, contributing to the development of insulin resistance in type-2 diabetes. This study investigates the relationship of glutamine metabolism with insulin resistance and ER stress under obese conditions. Using differentiated 3T3-L1 adipocytes, we demonstrate that increased glutamine supplementation enhances insulin sensitivity and reduces ER stress. Enhanced glutamine treatment also upregulated key amino acid transporters, Alanine-Serine-Cysteine Transporter 2 (ASCT2), L-type Amino Acid Transporter 1 (LAT1), and Cystine/Glutamate Antiporter (xCT), activating the mammalian target of rapamycin (mTOR) pathway. To investigate the specific role of ASCT2, its expression was reduced in 3T3-L1 fibroblasts via sh-ASCT2 transfection prior to adipogenic differentiation. Interestingly, the levels of other selected glutamine-glutamate transporters, LAT1 and xCT, were also decreased. Knockdown of ASCT2 via shRNA significantly impaired adipocyte differentiation. The significant reduction of intracellular lipid accumulation leads to decreased ER stress and insulin resistance in sh-ASCT2 adipocytes. Metabolomic analysis results revealed that intracellular glutamine and malate levels increased during fat cell differentiation. The glutamine levels decreased in sh-ASCT2 adipocytes, while malate levels remained unchanged. In conclusion, glutamine may enhance insulin sensitivity by modulating ER stress and influencing transporter expression. ASCT2 might play a role in adipocyte differentiation, and evidence indicates that ASCT2 inhibition could be associated with reduced adipogenesis and improved insulin signaling, suggesting its potential relevance as a therapeutic target in obesity-related insulin resistance. Further studies are needed to clarify the context-dependent mechanisms by which glutamine and ASCT2 regulate metabolic stress adaptation.