A new study suggests that a brain-hormone path involving leptin and insulin working together in specific cells in the hypothalamus region of the brain affects the regulation of blood sugar and thereby may explain how type 2 diabetes can arise without obesity and surprisingly, may also explain female fertility.
You can read about the research, led by the University of Texas (UT) Southwestern Medical Center in Dallas, in a 7 April online issue of Cell Metabolism.
Senior author Dr Joel Elmquist, professor of internal medicine and pharmacology at UT Southwestern, told the press that many people, including doctors, believe we develop type 2 diabetes only after obesity, but this study, which was performed on mice, suggests a person may not have to be obese to develop type 2 diabetes.
“We can make the animals very diabetic without obesity, suggesting that there may be a circuit or path of resistance to these signals in the brain that helps explain the powerful anti-diabetic actions of leptin,” explained Elmquist.
This study reveals that a group of brain cells called pro-opiomelanocortin (POMC) neurons play a role in regulating glucose and insulin independently of body weight and food intake.
POMC neurons exist in the hypothalamus, a small almond-sized region of the brain that sits just above the brain stem and among many things, helps to suppress appetite and induce weight loss.
Previous studies have shown that terminally ill rodents with type 1 diabetes can regain full health after receiving a single injection of leptin, a hormone made by the body’s fat cells. However, the cellular biology underlying this effect has not been clear.
Elmquist and colleagues already knew from previous studies that deleting only the leptin receptor in the POMC neurons leads to mild obesity but does not affect the control of blood sugar, while deleting only the insulin receptor has no effect on either body weight or blood sugar control.
So they genetically engineered laboratory mice so they did not have any leptin and insulin receptors in their POMC neurons, but kept them intact in other tissue and cell types, such as liver and ovaries.
The mice showed systemic insulin resistance and became severly diabetic, but they did not become obese, reported the researchers.
Elmquist said this indicates that leptin and insulin, when acting on POMC neurons, work together and can make up for each other’s absence. He said there appeared to be what he called a “functional redundancy” in the POMC neurons in respect of blood sugar regulation:
“We don’t know if the same neurons respond to both leptin and insulin, but it is clear that functionally leptin can compensate for a lack of insulin and vice versa,” said Elmquist.
A surprising finding was that the researchers also found that the female mice that had neither leptin nor insulin receptors in their POMC neurons had difficulty breeding and had smaller litters than counterparts that were missing only one of the receptors.
Speculating on the reason for this, the researchers suggested that missing both receptors may have caused the female mice to develop high levels of androgens, including the well-known male hormone testosterone.
Elmquist said he wasn’t an expert in endocrinology, but nonetheless he was not expecting to see this result.
He said this might be the first gentic model of polycystic ovary syndrome (PCOS), a metabolic disorder that is often accompanied by a range of symptoms in women, including obesity, excessive facial hair, and in more severe cases, infertility, diabetes and heart disease.
Elmquist and colleagues now want to further understand the role of POMC neurons, for instance how they control glucose production in the liver.
Grants from the American Diabetes Association, the Richard and Susan Smith Family Foundation, the NIH and the German research foundation DFG funded the study.
“Direct Insulin and Leptin Action on Pro-opiomelanocortin Neurons Is Required for Normal Glucose Homeostasis and Fertility.”
Jennifer W. Hill, Carol F. Elias, Makoto Fukuda, Kevin W. Williams, Eric D. Berglund, William L. Holland, You-Ree Cho, Jen- Chieh Chuang, Yong Xu, Michelle Choi, Danielle Lauzon, Charlotte E. Lee, Roberto Coppari, James A. Richardson, Jeffrey M. Zigman, Streamson Chua, Philipp E. Scherer, Bradford B. Lowell, Jens C. Brüning, Joel K. Elmquist.
Source: UT Southwestern.
Written by: Catharine Paddock, PhD