PEPCK1 Antisense Oligonucleotide Prevents Adiposity and Impairs Hepatic Glycogen Synthesis in High-Fat Male Fed Rats.

Abstract

The increased hepatic gluconeogenesis in type 2 diabetes mellitus has often been ascribed to increased transcription of phosphoenolpyruvate carboxykinase 1, cystolic form (PEPCK1), although recent evidence has questioned this attribution. To assess the metabolic role of PEPCK1, we treated regular chow fed and high-fat fed (HFF) male Sprague-Dawley rats with a 2'-O-methoxyethyl chimeric antisense oligonucleotide (ASO) against PEPCK1 and compared them with control ASO-treated rats. PEPCK1 ASO effectively decreased PEPCK1 expression in the liver and white adipose tissue. In chow fed rats, PEPCK1 ASO did not alter adiposity, plasma glucose, or insulin. In contrast, PEPCK1 ASO decreased the white adipose tissue mass in HFF rats but without altering basal rates of lipolysis, de novo lipogenesis, or glyceroneogenesis in vivo. Despite the protection from adiposity, hepatic insulin sensitivity was impaired in HFF PEPCK1 ASO-treated rats. PEPCK1 ASO worsened hepatic steatosis, although without additional impairments in hepatic insulin signaling or activation of inflammatory signals in the liver. Instead, the development of hepatic insulin resistance and the decrease in hepatic glycogen synthesis during a hyperglycemic clamp was attributed to a decrease in hepatic glucokinase (GCK) expression and decreased synthesis of glycogen via the direct pathway. The decrease in GCK expression was associated with increased expression of activating transcription factor 3, a negative regulator of GCK transcription. These studies have demonstrated that PEPCK1 is integral to coordinating cellular metabolism in the liver and adipose tissue, although it does not directly effect hepatic glucose production or adipose glyceroneogenesis.

• Authors: Sara A Beddow, Arijeet K Gattu, Daniel F Vatner, Lauren Paolella, Abdulelah Alqarzaee, Nedda Tashkandi, Violeta B Popov, Christopher D Church, Matthew S Rodeheffer, Gary W Cline, John G Geisler, Sanjay Bhanot, Varman T Samuel
• Journal: Endocrinology (Endocrinology) Vol. 160 Issue 1 Pg. 205-219 (01 01 2019) ISSN: 1945-7170 [Electronic] United States
• PMID: 30445425 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Insulin
• Intracellular Signaling Peptides and Proteins
• Liver Glycogen
• Oligonucleotides, Antisense
• Glucokinase
• Pck1 protein, rat
• Phosphoenolpyruvate Carboxykinase (GTP)

Topics

• Adipose Tissue, White (metabolism)
• Adiposity
• Animals
• Diabetes Mellitus, Type 2 (enzymology, genetics, metabolism, physiopathology)
• Diet, High-Fat (adverse effects)
• Glucokinase (genetics, metabolism)
• Humans
• Insulin (metabolism)
• Intracellular Signaling Peptides and Proteins (genetics, metabolism)
• Lipogenesis
• Liver (metabolism)
• Liver Glycogen (biosynthesis)
• Male
• Mice
• Mice, Inbred C57BL
• Oligonucleotides, Antisense (genetics)
• Phosphoenolpyruvate Carboxykinase (GTP) (genetics, metabolism)
• Rats
• Rats, Sprague-Dawley