Central melanocortin receptor agonist reduces hepatic lipogenic gene expression in streptozotocin-induced diabetic mice
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Published on: September 9, 2021
Arnold Leckstrom1, Pei San Lew, Nicole J Poritsanos
1Department of Physiology, University of Manitoba, Winnipeg, Manitoba, Canada R3E 0J9.
Aims:
The central melanocortin system regulates a variety of metabolic functions including lipid metabolism and hepatic lipogenic gene expression. The objective of the present study was to determine whether central melanocortin regulates hepatic lipogenic gene expression under insulin insufficient condition.
Main Methods:
We examined the effect of intracerebroventricular (i.c.v.) injection of MTII, a melanocortin agonist, on hepatic gene expression in a mouse model of the insulin-deficient diabetes. Diabetes was induced in male C57BL/6J mice by intraperitoneal injections of streptozotocin (STZ). Diabetic mice received daily i.c.v. injections of MTII (3 nmol) for 11 days. Hepatic expression levels of lipogenic genes and their transcription factors were measured.
Key Findings:
MTII treatment significantly reduced hepatic expression levels of genes encoding lipid biosynthetic enzymes, stearoyl-CoA desaturase 1 (SCD1), glycerol-3-phosphate acyltransferase 1 (GPAT1), acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1), and DGAT2 mRNA without significant changes in serum insulin levels, homeostasis model-assessment of insulin resistance (HOMA-IR) and glucose tolerance in STZ-induced diabetic mice. MTII treatment also reduced fatty acid synthase (FAS) and SCD1 protein levels in the liver of diabetic mice. Expression levels of genes encoding transcription factors of these lipogenic genes, sterol regulatory element-binding protein 1c (SREBP-1c) and peroxisome proliferator-activated receptor γ2 (PPARγ2) were also significantly reduced by MTII treatment.
Significance:
These data suggest that the insulin-independent mechanism is involved in the regulation of hepatic lipogenic gene expression. Enhanced central melanocortin signaling may be effective in improving abnormal lipid metabolism associated with insulin-deficiency or insulin-insufficiency.
Insights
Central melanocortin signaling reduces hepatic lipogenic gene expression in diabetic mice, independent of insulin levels. This suggests enhanced melanocortin pathways may improve lipid metabolism in insulin deficiency.
Area of Science:
- Metabolic regulation
- Endocrinology
- Molecular biology
Background:
- The central melanocortin system plays a key role in regulating metabolic functions, including lipid metabolism and hepatic lipogenic gene expression.
- Understanding how this system influences hepatic gene expression under conditions of insulin insufficiency is crucial for metabolic disease research.
Purpose of the Study:
- To investigate the effect of central melanocortin signaling on hepatic lipogenic gene expression in a mouse model of insulin-deficient diabetes.
- To determine if melanocortin regulation of hepatic lipogenesis occurs independently of insulin levels.
Main Methods:
- Induction of diabetes in male C57BL/6J mice using streptozotocin (STZ).
- Intracerebroventricular (i.c.v.) administration of melanocortin agonist MTII (3 nmol) daily for 11 days in diabetic mice.
- Measurement of hepatic expression levels of key lipogenic genes (SCD1, GPAT1, DGAT1, DGAT2, FAS) and their transcription factors (SREBP-1c, PPARγ2).
Main Results:
- MTII treatment significantly reduced mRNA levels of hepatic lipogenic enzymes (SCD1, GPAT1, DGAT1, DGAT2) and fatty acid synthase (FAS) in diabetic mice.
- Protein levels of fatty acid synthase (FAS) and stearoyl-CoA desaturase 1 (SCD1) were also decreased by MTII treatment.
- Expression of transcription factors sterol regulatory element-binding protein 1c (SREBP-1c) and peroxisome proliferator-activated receptor γ2 (PPARγ2) was significantly downregulated by MTII, without altering serum insulin, HOMA-IR, or glucose tolerance.
Conclusions:
- Central melanocortin signaling regulates hepatic lipogenic gene expression through an insulin-independent mechanism.
- Enhanced central melanocortin signaling shows potential for improving abnormal lipid metabolism in states of insulin deficiency or insufficiency.
