The role of C16:0 ceramide in the development of obesity and type 2 diabetes: CerS6 inhibition as a novel therapeutic approach

Autor: Maximilian Bielohuby, Bodo Brunner, Jens C. Brüning, Anja Pfenninger, Norbert Tennagels, Philip Just Larsen, Gitte Hansen, Bing Wang, Suryaprakash Raichur
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Blood Glucose
Leptin
Male
0301 basic medicine
Mice
Obese
Adipose tissue
Type 2 diabetes
Weight Gain
Mice
chemistry.chemical_compound
0302 clinical medicine
Adipose Tissue
Brown
Sphingosine N-Acyltransferase
Antisense oligonucleotide
Ceramide synthase
Leptin Deficiency
Chemistry
Hep G2 Cells
Liver
Gene Knockdown Techniques
Original Article
medicine.medical_specialty
Ceramide
lcsh:Internal medicine
030209 endocrinology & metabolism
Ceramides
Diet
High-Fat
03 medical and health sciences
Insulin resistance
Internal medicine
medicine
Animals
Humans
Obesity
lcsh:RC31-1245
Molecular Biology
Sphingolipids
Membrane Proteins
Cell Biology
Oligonucleotides
Antisense
Thionucleotides
medicine.disease
Sphingolipid
Mice
Inbred C57BL
Disease Models
Animal
030104 developmental biology
Endocrinology
Diabetes Mellitus
Type 2
Zdroj: Molecular Metabolism, Vol 21, Iss, Pp 36-50 (2019)
Molecular Metabolism
ISSN: 2212-8778
Popis: Objective Ectopic fat deposition is associated with increased tissue production of ceramides. Recent genetic mouse studies suggest that specific sphingolipid C16:0 ceramide produced by ceramide synthase 6 (CerS6) plays an important role in the development of insulin resistance. However, the therapeutic potential of CerS6 inhibition not been demonstrated. Therefore, we pharmacologically investigated the selective ablation of CerS6 using antisense oligonucleotides (ASO) in obese insulin resistance animal models. Methods We utilized ASO as therapeutic modality, CerS6 ASO molecules designed and synthesized were initially screened for in-vitro knock-down (KD) potency and cytotoxicity. ASOs with >85% inhibition of CerS6 mRNA were selected for further investigations. Most promising ASOs verified for in-vivo KD efficacy in healthy mice. CerS6 ASO (AAGATGAGCCGCACC) was found most active with hepatic reduction of CerS6 mRNA expression. Prior to longitudinal metabolic studies, we performed a dose titration target engagement analysis with CerS6 ASO in healthy mice to select the optimal dose. Next, we utilized leptin deficiency ob/ob and high fat diet (HFD) induced obese mouse models for pharmacological efficacy study. Results CerS6 expression were significantly elevated in the liver and brown adipose, this was correlated with significantly elevated C16:0 ceramide concentrations in plasma and liver. Treatment with CerS6 ASO selectively reduced CerS6 expression by ∼90% predominantly in the liver and this CerS6 KD resulted in a significant reduction of C16:0 ceramide by about 50% in both liver and plasma. CerS6 KD resulted in lower body weight gain and accompanied by a significant reduction in whole body fat and fed/fasted blood glucose levels (1% reduction in HbA1c). Moreover, ASO-mediated CerS6 KD significantly improved oral glucose tolerance (during oGTT) and mice displayed improved insulin sensitivity. Thus, CerS6 appear to play an important role in the development of obesity and insulin resistance. Conclusions Our investigations identified specific and selective therapeutic valid ASO for CerS6 ablation in in-vivo. CerS6 should specifically be targeted for the reduction of C16:0 ceramides, that results in amelioration of insulin resistance, hyperglycemia and obesity. CerS6 mediated C16:0 ceramide reduction could be a potentially attractive target for the treatment of insulin resistance, obesity and type 2 diabetes.
Highlights • Designed, screened and discovered therapeutic CerS6 ASO that specifically and selectively inhibits CerS6 in in-vivo. • Therapeutic inhibition of a selective enzyme (CerS6) ameliorate insulin resistance and hyperglycemia. • In-vivo selective ablation of CerS6 protected from body weight gain (∼25% body weight reduction in HFD obese mice). • CerS6 could be a potentially attractive target for the treatment of insulin resistance, obesity and type 2 diabetes.
Databáze: OpenAIRE
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