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UT Southwestern researchers uncover new brain pathways for understanding Type 2 diabetes and obesity.

Researchers at UT Southwestern Medical Center have identified neural pathways that increase understanding of how the brain regulates body weight, energy expenditure, and blood glucose levels, a discovery that can lead to new therapies for treating Type 2 diabetes and obesity.  The study found that melanocortin 4 receptors (MC4Rs) expressed by neurons that control the autonomic nervous system are key in regulating glucose metabolism and energy expenditure.

A number of previous studies have demonstrated that MC4Rs are key regulators of energy expenditure and glucose homeostasis, but the key neurons required to regulate these responses were unclear.  In the current study the researchers found that expression of these receptors by neurons that control the sympathetic nervous system, seem to be key regulators of metabolism. In particular, these cells regulate blood glucose levels and the ability of white fat to become ‘brown or beige’ fat.

Using mouse models, the team of researchers deleted MC4Rs in neurons controlling the sympathetic nervous system. This manipulation lowered energy expenditure and subsequently caused obesity and diabetes in the mice. The finding demonstrates that MC4Rs are required to regulate glucose metabolism, energy expenditure, and body weight, including thermogenic responses to diet and exposure to cold. Understanding this pathway in greater detail may be a key to identifying the exact processes in which type 2 diabetes and obesity are developed independently of each other.

In 2006 the team collaboratede with Harvard Medical School to discover that MC4Rs in other brain regions control food intake but not energy expenditure.

The American Diabetes Association lists Type 2 diabetes as the most common form of diabetes. The disease is characterised by high blood glucose levels caused by the body’s lack of insulin or inability to use insulin efficiently, and obesity is one of the most common causes. Future studies by the team will examine how melanocortin receptors may lead to the ‘beiging’ of white adipose tissue, a process that converts white adipose to energy-burning brown adipose tissue.

Source:  UT Southwestern Medical Center

 

Melanocortin 4 receptors (MC4Rs) in the central nervous system are key regulators of energy and glucose homeostasis. Notably, obese patients with MC4R mutations are hyperinsulinemic and resistant to obesity-induced hypertension. Although these effects are probably dependent upon the activity of the autonomic nervous system, the cellular effects of MC4Rs on parasympathetic and sympathetic neurons remain undefined. Here, we show that MC4R agonists inhibit parasympathetic preganglionic neurons in the brainstem. In contrast, MC4R agonists activate sympathetic preganglionic neurons in the spinal cord. Deletion of MC4Rs in cholinergic neurons resulted in elevated levels of insulin. Furthermore, re-expression of MC4Rs specifically in cholinergic neurons (including sympathetic preganglionic neurons) restores obesity-associated hypertension in MC4R null mice. These findings provide a cellular correlate of the autonomic side effects associated with MC4R agonists and demonstrate a role for MC4Rs expressed in cholinergic neurons in the regulation of insulin levels and in the development of obesity-induced hypertension.  Elmquist et al 2012.
Melanocortin 4 receptors (MC4Rs) in the central nervous system are key regulators of energy and glucose homeostasis. Notably, obese patients with MC4R mutations are hyperinsulinemic and resistant to obesity-induced hypertension. Although these effects are probably dependent upon the activity of the autonomic nervous system, the cellular effects of MC4Rs on parasympathetic and sympathetic neurons remain undefined. Here, we show that MC4R agonists inhibit parasympathetic preganglionic neurons in the brainstem. In contrast, MC4R agonists activate sympathetic preganglionic neurons in the spinal cord. Deletion of MC4Rs in cholinergic neurons resulted in elevated levels of insulin. Furthermore, re-expression of MC4Rs specifically in cholinergic neurons (including sympathetic preganglionic neurons) restores obesity-associated hypertension in MC4R null mice. These findings provide a cellular correlate of the autonomic side effects associated with MC4R agonists and demonstrate a role for MC4Rs expressed in cholinergic neurons in the regulation of insulin levels and in the development of obesity-induced hypertension. Elmquist et al 2012.

 

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One thought on “UT Southwestern researchers uncover new brain pathways for understanding Type 2 diabetes and obesity. Leave a comment

  1. Most of those suffering from this disease complain of weakness, giddiness, and body
    ache. Your long term health as well as your long
    term weight matter. It is important that you do
    various physical activities daily so you will not gain much weight.

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