Downregulation of the acetyl-CoA metabolic network in adipose tissue of obese diabetic individuals and recovery after weight loss.

Abstract

AIMS/HYPOTHESIS:

Not all obese individuals develop type 2 diabetes. Why some obese individuals retain normal glucose tolerance (NGT) is not well understood. We hypothesise that the biochemical mechanisms that underlie the function of adipose tissue can help explain the difference between obese individuals with NGT and those with type 2 diabetes.

METHODS:

RNA sequencing was used to analyse the transcriptome of samples extracted from visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) of obese women with NGT or type 2 diabetes who were undergoing bariatric surgery. The gene expression data was analysed by bioinformatic visualisation and statistical analyses techniques.

RESULTS:

A network-based approach to distinguish obese individuals with NGT from obese individuals with type 2 diabetes identified acetyl-CoA metabolic network downregulation as an important feature in the pathophysiology of type 2 diabetes in obese individuals. In general, genes within two reaction steps of acetyl-CoA were found to be downregulated in the VAT and SAT of individuals with type 2 diabetes. Upon weight loss and amelioration of metabolic abnormalities three months following bariatric surgery, the expression level of these genes recovered to levels seen in individuals with NGT. We report four novel genes associated with type 2 diabetes and recovery upon weight loss: ACAT1 (encoding acetyl-CoA acetyltransferase 1), ACACA (encoding acetyl-CoA carboxylase α), ALDH6A1 (encoding aldehyde dehydrogenase 6 family, member A1) and MTHFD1 (encoding methylenetetrahydrofolate dehydrogenase).

CONCLUSIONS/INTERPRETATION:

Downregulation of the acetyl-CoA network in VAT and SAT is an important feature in the pathophysiology of type 2 diabetes in obese individuals. ACAT1, ACACA, ALDH6A1 and MTHFD1 represent novel biomarkers in adipose tissue associated with type 2 diabetes in obese individuals.

• Authors: Harish Dharuri, Peter A C 't Hoen, Jan B van Klinken, Peter Henneman, Jeroen F J Laros, Mirjam A Lips, Fatiha El Bouazzaoui, Gert-Jan B van Ommen, Ignace Janssen, Bert van Ramshorst, Bert A van Wagensveld, Hanno Pijl, Ko Willems van Dijk, Vanessa van Harmelen
• Journal: Diabetologia (Diabetologia) Vol. 57 Issue 11 Pg. 2384-92 (Nov 2014) ISSN: 1432-0428 [Electronic] Germany
• PMID: 25099943 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Minor Histocompatibility Antigens
• Acetyl Coenzyme A
• MTHFD1 protein, human
• Methylenetetrahydrofolate Dehydrogenase (NADP)
• ACAT1 protein, human
• Acetyl-CoA C-Acetyltransferase
• ACACA protein, human
• Acetyl-CoA Carboxylase

Topics

• Acetyl Coenzyme A (metabolism)
• Acetyl-CoA C-Acetyltransferase (genetics)
• Acetyl-CoA Carboxylase (genetics)
• Adipocytes (metabolism)
• Adipose Tissue (metabolism)
• Adult
• Diabetes Mellitus, Type 2 (metabolism)
• Female
• Humans
• Intra-Abdominal Fat (metabolism)
• Male
• Methylenetetrahydrofolate Dehydrogenase (NADP) (genetics)
• Middle Aged
• Minor Histocompatibility Antigens
• Obesity (enzymology, metabolism)
• Sequence Analysis, RNA
• Weight Loss (physiology)