O-GLCNACYLATION IS NOT INCREASED IN THE HYPOTHALAMUS OF RATS GIVEN 6 WEEK ACCESS TO SUCROSE SOLUTION DESPITE MARKERS OF METABOLIC DYSREGULATION

Abstract

The peptide hormone leptin acts globally to maintain various metabolic processes.

Impaired response to leptin binding is referred to as leptin resistance and results in

metabolic dysregulation. Leptin is essential in the prevention of weight gain through

central signals to increase energy expenditure and reduce food intake. A sugar

sensitive pathway, the hexosamine biosynthesis pathway (HBP), may be the cause of

diet induced leptin resistance. The HBP glycosylates proteins by modifying fructose-

6-phosphate molecules from glycolysis. While high sugar diets have been linked to

leptin resistance, O-GlcNAcylation of pathway proteins have not been examined.

Approximately 8-week-old male rats were assigned to ad libitum access to diet and

water or 30% sucrose solution, diet and water. On Day 5 rats were surgically fitted

with a third ventricle cannula. On Day 41, diet and sugar solutions were removed for

an overnight fast. On Day 42 each rat received a central injection of leptin or control

solution and subsequently euthanized 30 minutes post injection. Body weight and

body composition were not significantly different between treatment groups after 42

days. However, the Sucrose group exhibited signs of metabolic syndrome, evidenced

by increased fasting serum triglycerides and glucose as well as decreased serum

HDL. Analysis of hypothalamic O-GlcNAcylation revealed no significant difference

between treatment groups. These data may be the result of variability of glucose

utilization within the hypothalamus. These data support previous findings that 42-day

access to a 30% sucrose solution yields evidence of metabolic syndrome in the

absence of obesity as well as the absence of increased hypothalamic OGlcNAcylation.

Future research should examine O-GlcNAcylation regionally within

the hypothalamus. Analysis of protein specific O-GlcNAcylation was not achieved;

however, a novel O-GlcNAcylation was observed in hypothalamic tissue at the

Threonine 1808 residue of prolow-density lipoprotein receptor-related protein 1

isoform X1 (LRP-1), a protein that may play a crucial role in leptin signaling. These

data give further evidence to support the use of 30% sucrose solution to model leptin

resistance in Sprague Dawley rats, as well as provide a target protein for future

analysis.