By Jamshed Arslan, Pharm. D., PhD.
The hypothalamus is an insulin receptor-rich brain region. Insulin receptor signaling in the CNS can regulate blood pressure, for example, by increasing sympathetic outflow to the cardiovascular organs. However, the cardiometabolic impact of deleting insulin receptors only in the hypothalamic region is different from deleting insulin receptors in the whole brain. In other words, insulin signaling outside the hypothalamus is also important for cardioregulatory activities. To explore this extra-hypothalamic insulin signaling, scientists from Cornell University, NY , and George Washington University, Washington DC , focused on the subfornical organ because of three main reasons:
- The subfornical organ has insulin receptors.
- The subfornical organ is a part of the forebrain devoid of blood-brain barrier, hence it can sense circulating factors like insulin.
- The subfornical organ has several projections towards cardiometabolic nuclei like the hypothalamus, indicating a potential for regulating cardiovascular functions .
The researchers in this study reported how selective deletion of subfornical organ insulin receptors in mice influences cardiometabolic parameters, such as blood pressure, heart rate, weight gain, adiposity and hypertriglyceridemia. Based on this, the team concluded that subfornical organ insulin receptors modulate cardiometabolic function and their deficiency can lead to metabolic syndrome .
Food intake-independent weight gain after selective deletion of insulin receptors in subfornical organ
After histochemical confirmation of insulin receptors in the subfornical organ, the investigators sought to explore the functional role these receptors could play in metabolism. Investigators selectively deleted subfornical organ insulin receptors in mice using Cre recombinase. They observed significantly greater weight gain and white adipose tissues in knockout mice than the controls, irrespective of the food intake over the course of 10 weeks. Leading the team to conclude that subfornical organ insulin signaling protects against weight gain and adiposity in a calorie-independent manner. Next, the team wanted to evaluate any abnormal retention of lipids in the liver, since hepatic steatosis can be one of the key features of metabolic syndrome.
Hepatic steatosis, defined as intrahepatic accumulation of fat, is associated with inflammation and metabolic liver malfunction. Various mechanisms may contribute to hepatic steatosis including elevated hepatic fatty acid flow, abnormal fatty acid clearance and increased de novo lipogenesis. Diagram from Metabolic Syndrome Signaling Poster , published in its original form in a collaborative between Dr. Robert H. Lustig, Dr. Alejandro Gugliucci and Bio-Techne Corporation.
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Deleting subfornical organ insulin receptors promotes hepatic steatosis and lowers arterial blood pressure
To explore the impact of deleting subfornical organ insulin receptors, liver weight and triglyceride levels were measured. Ten weeks following the Cre-mediated deletion of subfornical organ insulin receptors, hepatic triglycerides were about four times higher in the knockout mice than the controls, despite similar liver weights. As expected, blood triglyceride levels were also higher in the knockouts.
Besides noticing hypertriglyceridemia and hepatic steatosis, the researchers constantly monitored heart rate and blood pressure to determine the cardiovascular impact of removing subfornical organ insulin receptors. Radiotelemetry measurements indicated a chronic decline in mean arterial blood pressure in the knockout mice relative to the controls, but heart rate and systolic blood pressure did not differ much. In sum, subfornical organ insulin signaling is responsible for sensing, integrating and regulating cardiometabolic state of the body.
Significance and future direction
This is the first study to indicate that the subfornical organ can work independently or in collaboration with the hypothalamus in insulin-mediated metabolism. Further investigations stemming from this research could focus on discrete subpopulation of neurons in the subfornical organ which may control distinct aspects of cardiometabolic outcome of insulin signaling.
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Jamshed Arslan, Pharm D, PhD
Dr. Arslan is an Assistant Professor at Dow University of Health Sciences, Pakistan,
where he teaches Pharmacology to future pharmacists.
Kwon Jeong, J., Horwath, J. A., Simonyan, H., Blackmore, K. A., & Butler, S. D. (2019). Subfornical organ insulin receptors tonically modulate cardiovascular and metabolic function. Physiological Genomics. https://doi.org/10.1152/physiolgenomics.00021.2019