News & Research

    Columbia University Medical Center, New York, New York

Model of maternal obesity to study effects on developing hypothalamic circuits that promote obesity in progeny and re-programming these adverse outcomes in young mice

General Research Subject: Gestational Diabetes

Focus: Obesity\Animal Models, Other, Pediatrics\Obesity

Type of Grant: Basic Science

Project Start Date: July 1, 2011

Project End Date: June 30, 2014

Research Description

The prevalence of childhood obesity and type 2 diabetes (T2D) are rising rapidly.  Genetic changes cannot, and environmental factors may not, be sufficient to account for the rapidity of these changes.  Intrauterine/early postnatal events can influence the development of the neuronal circuits in the brain that control food intake and metabolism, thereby potentially exerting a permanent impact on the metabolic status of the progeny.  As the number of obese and diabetic women of childbearing age has increased, so has the potential for detrimental influences of deranged maternal metabolic status during gestation and lactation on susceptibility to obesity and T2D in progeny. The proposed studies will use a mouse model of maternal obesity/high fat diet (HFD) to investigate how maternal factors could affect susceptibility to obesity and T2D in the progeny.  This model will be used to assess the effects of maternal diet on two functionally distinct groups of neurons in the feeding circuit.  In parallel, obese offspring of HFD-fed mothers will be used as starting point to examine whether maternally-programmed obesity can be reduced by dietary interventions in young animals. These studies should provide important insights into how maternal metabolic status is conveyed to their offspring, and whether dietary interventions in young animals can reduce obesity that is maternally-programmed.  These experiments represent an important step in the defining the relevant maternal signals that promote obesity in offspring and could lead to the design of novel strategies to prevent obesity/T2DM in humans.

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 aim of my research is to understand how exposure to a high fat diet (HFD) at different developmental   stages influences susceptibility to obesity/type 2 diabetes (T2D).  The prevalence of childhood obesity and T2D are rising rapidly.  The trajectory of this upsurge is very steep in some populations- with obesity rates increasing by as much as 60% between 1988 and 2000.  Genetic changes cannot, and postnatal environmental factors may not, be sufficient to account for the rapidity of these changes.  There is mounting evidence to support the idea that one “accelerant” to obesity/T2D susceptibility is the metabolic environment provided by the mother.  As the number of obese and diabetic women of childbearing age has increased, so has the potential for detrimental influences of compromised maternal metabolic status during gestation and lactation on susceptibility to obesity and T2D in progeny. 

The proposed studies will use a mouse model of maternal obesity/HFD feeding to investigate how maternal factors could affect susceptibility to obesity and T2D in the progeny.  This model will be used to assess the effects of maternal diet on two functionally distinct groups of neurons in the feeding circuit.  In parallel, obese offspring of HFD-fed mothers will be used as starting point to examine whether maternally-programmed obesity can be reduced by dietary interventions in young animals. These studies should provide important insights into how maternal metabolic status is conveyed to their offspring, and whether dietary interventions in young animals can reduce obesity that is maternally-programmed.  These experiments represent an important step in the defining the relevant maternal signals that promote obesity in offspring and could lead to the design of novel strategies to prevent obesity/T2DM in humans.

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

My project addresses issues related to maternal transmission of increased susceptibility to obesity/T2D, as well as whether behavioral interventions in young children can reverse some of the adverse metabolic consequences due to maternal programming. Therefore, our work may ultimately benefit several distinct populations.  Understanding how the gestational environment influences metabolic outcomes in offspring could lead to novel strategies to reduce the transmission of obesity/T2D susceptibility.  As increased prevalence of obesity has been reported in the offspring of both type 1 and type 2 diabetics, our studies could benefit women of child-bearing age in both populations.

The second major goal of the project is to determine whether behavioral interventions in obese young animals can lead to sustained improvements in metabolic outcomes.  In studies using a genetic model of early-onset hyperphagia and obesity, my lab found that pair-feeding males to the intake of controls from 3-10 weeks of age permanently increased basal metabolic rate, which resulted in reduced adiposity-related phenotypes without impairing linear growth.  These studies will examine whether re-programming of basal metabolic rate can also be achieved in a wild-type model.  If proven true, these studies could lead to the design of more efficacious strategies to combat childhood obesity.

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

I have been involved in diabetes research for over fifteen years. Trained as an Ophthalmologist and a retinal specialist, I have encountered numerous patients with diabetic retinopathy, a devastating disease that causes vision loss in adults. In contrast to the increasing diabetic retinopathy rate due to the rising epidemic of diabetes, very limited reliable therapies are available for treating this disease. I believe that developing new effective therapies for diabetic retinopathy is urgently needed, and that understanding the molecular mechanisms how diabetes causes damage to retinal cells, and, thus, identifying critical genes that mediate the damage is the key for developing new drugs. This award will enable us to address these foremost important questions: 1) understand the mechanisms of diabetic retinopathy; 2) discover a novel pathogenic gene of diabetes-induced vascular damage. We anticipate that this project will generate important information that helps us to seek novel and effective ways to prevent and treat diabetic retinopathy.

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

As the prevalence of diabetes has increased dramatically, I think that the problem is beginning to attract scientists from other disciplines, which will strengthen the overall diabetes research effort.  I believe that cross-disciplinary research into the neurobiology of obesity/T2D will provide novel insights into causes and potential treatments for obesity, diabetes and associated medical conditions.  Thus, research into the molecular physiology of obesity and diabetes should be combined with fields such as developmental, molecular and behavioral neuroscience. I propose to use my ADA Research Award for this purpose.

I feel that diabetes research effort would be greatly advanced by the recruitment of scientists with diverse scientific backgrounds and the establishment of pilot grants to encourage multi-disciplinary collaborations.  As a developmental neurobiologist in the Naomi Berrie Diabetes Center at Columbia University, I have had a unique opportunity to learn how to apply my interest in brain development to study metabolic outcomes.  For most other neuroscientists, the hurdles required to enter the field of obesity/T2D research are much harder to overcome.  I think that the ADA should make it easier for scientists in other disciplines to initiate research projects related to diabetes under the guidance of suitable mentors.