News & Research

    Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts

Anti-diabetic actions of leptin via hypothalamic POMC and AgRP neruons

General Research Subject: Both Type 1 And Type 2 Diabetes

Focus: Obesity, Obesity\Animal Models, Signal Transduction (Non-Insulin Action), Signal Transduction (Non-Insulin Action)\Hormones, Signal Transduction (Non-Insulin Action)\Transgenic Models

Type of Grant: Basic Science

Project Start Date: July 1, 2012

Project End Date: June 30, 2015

Research Description

Leptin is a hormone that is produced in fat and acts in the brain to reduce food intake and bodyweight, and to improve glucose balance. Importantly, recent research shows that leptin can prevent or cure Type1 and Type 2 diabetes in rodents. However the underlying mechanisms are largely unknown. Elucidation of these crucial questions holds significant promise for the identification of novel diabetes drug targets.

Using a genetic approach, we have recently reported that leptin signaling via a small group of hypothalamic neurons is remarkably sufficient to entirely normalize hyperglycemia of the severely diabetic and massively obese db/db mouse. We showed that this effect was independent of leptin's effect on body weight. Other studies have shown that leptin can also correct diabetes in insulin-deficient Type 1 diabetic mouse models.

We will here utilize a number of genetic mouse models to investigate how leptin acts via the brain to improve or entirely prevent Type 1 and Type 2 diabetes in mice. Specifically, we will first determine if other hypothalamic neurons can also mediate glucose control by leptin. Secondly, we will identify the specific neuropeptides and neurotransmitters that are produced by those identified neurons and are responsible for mediating glucose control by leptin. Obtained data are important for advancing our understanding of how leptin and the brain controls peripheral glucose balance. The results are relevant for the identification of new anti-diabetes CNS pathways and for the potential development of leptin as a glucose-lowering drug in humans suffering from diabetes.

Research Profile

What area of diabetes research does your project cover?  What role will this particular project play in preventing, treating and/or curing diabetes?

The goals of this research project are to increase our understanding of the causes of Type 2 Diabetes Mellitus and to identify new mechanisms/pathways in the brain that control blood sugar levels. I will study how the hormone leptin is able to improve glucose balance in severely obese and diabetic rodents. We have recently discovered that leptin signaling within a small group of neurons, called POMC-neurons, in the brain of extremely obese and severely diabetic mice can remarkably cure their diabetes. We also show that the normalization of blood glucose happens independently of a reduction in caloric intake and body weight. Based on these data we conclude that a system exists in the brain that has a major capacity to influence blood glucose levels. We will here further investigate this pathway and determine if other neurons, namely AgRP neurons, have the same capacity. In addition, we aim to identify which neuronal outputs from those neurons, e.g. neuropeptides and neurotransmitters, are responsible for leptin’s anti-diabetic actions in this mouse model.

The results from this project will advance our understanding of a new signaling system in the brain that has major beneficial effects on lowering blood glucose levels in the setting of obesity and Type 2 Diabetes Mellitus in rodent models. Ultimately, findings from this proposal may lead to the identification of novel anti-diabetes drug-targets in the brain.

If a person with diabetes were to ask you how your project will help them in the future, how would you respond?

I would tell the patient that my project aims to search in the brain for novel ways to control blood glucose and prevent diabetes. More specifically, we aim to better understand how a natural hormone called leptin acts in the brain to control glucose balance, and I would explain that we have already demonstrated that we can remarkably prevent diabetes in extremely diabetic and very obese mice, without loss of weight. Thus, a brain pathway exists that directly controls glycemia. This new project will help us further understand exactly how leptin acts in the brain to exert anti-diabetic effects. With such new information we hope to help identify new drug targets that will eventually help humans suffering from diabetes.

Why is it important for you, personally, to become involved in diabetes research?  What role will this award play in your research efforts?

I first became directly involved in diabetes research in 1990 when I started my PhD studies with chief-physician Dr. Oluf Pedersen at Steno Diabetes Center in Denmark. The goal was to identify genetic defects involved in the development of insulin resistance in skeletal muscle of patients with type 2 diabetes. Working with medical doctors in a diabetes hospital next to basic scientists and on the same time being under the umbrella of a pharmaceutical company, namely Novo Nordisk – a major producer of insulin, was an immensely stimulating environment that very rapidly gave me a clear purpose in my working life. The feeling of performing experiments that could eventually help human disease continues to be very rewarding.

Despite major progress in diabetes treatments for humans over several decades, more than 40% of patients diagnosed with diabetes in the US do not achieve accepted glycemic targets. Thus, improved treatments are urgently needed. I want to help lead this push forward.

Since 1996, I have been a faculty member of the Endocrine Division at BIDMC and Harvard Medical School. This ADA Research Award is absolutely necessary for me to be able to proceed with the proposed experiments. I do not have other sources of research funding that would enable me to pay for supplies, animals or salaries for this project. I am therefore truly thrilled and excited to move forward with the planned studies and to complete these in a timely manner.

In what direction do you see the future of diabetes research going?

Important scientific developments over the past years show a major role of the brain in glucose control and development of diabetes in rodents. I foresee major future efforts to further understand the role of the brain in regulation of energy balance and glucose homeostasis, using animal models and eventually understand how these may be linked in patients with Type 2 diabetes. The understanding of the anti-diabetic actions of the brain is a new frontier in the development of new anti-diabetes drugs.