News & Research

    Baylor College of Medicine, Houston, Texas

Estrogen receptor alpha in male brains regulates energy homeostasis

General Research Subject: Obesity

Focus: Integrated Physiology\Regulation of Food Intake, Obesity\Animal Models, Pediatrics\Obesity

Type of Grant: Basic Science

Project Start Date: January 1, 2011

Project End Date: December 31, 2013

Research Description

Obesity is a major risk factor for type II diabetes and increased understanding of body weight regulation may lead to effective strategies to combat obesity and diabetes. The sex hormone, estrogen, plays a beneficial role in maintaining normal body weight not only in women but also in men. Although numerous investigators have been trying to determine mechanisms by which estrogen regulates energy balance in females, relatively less effort is devoted to understanding how estrogen acts in males to maintain normal body weight. Pilot studies showed that male mice lacking estrogen receptor α (ER α) in a subset of neurons (Phox2b neurons) in the brain develop obesity, while female mice with the same mutation are normal.

These raise the possibility that estrogen acts on these specific neurons in the male brains to provide anti-obesity benefits. Objectives of the current grant include to determine the physiological roles of ER α expressed by Phox2b neurons in male brains in the regulation of energy balance and to evaluate the role of these ERαneurons in mediating the metabolic effects of neonatal exposure to phytoestrogens. In addition, a series of experiments are designed to explore the mechanisms underlying the anti-obesity effects of ER α in male brains and to identify the biological origin of estrogen that acts on these ER α neurons. Thus, these experiments may reveal novel mechanisms underlying the metabolic benefits of estrogen in males and may provide experimental basis for the application of estrogen and its analogs to treat obesity and cardiovascular disorders in men.

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?

Obesity is now recognized as a serious global health problem. Over 30% of Americans are obese and 60% are overweight. Obese individuals are at an increased risk for developing type II diabetes, and obesity is associated with 300,000 premature deaths every year. These figures highlight the urgent need to better understand the etiology of obesity and to develop more effective therapies to combat obesity and ultimately prevent metabolic disorders, e.g. diabetes.

My project will be focused on the mechanisms underlying the anti-obesity effects of estrogen and its receptors in male brains. Estrogen receptor α (ER α) regulates body weight in men with unknown mechanisms. Male (but not female) mice with ER α deleted selectively in hindbrain Phox2b neurons (deletion mice), developed early-onset obesity. This led to a hypothesis that aromatase-originated estrogen acts upon ERα in male phox2b neurons to control energy homeostasis. The following specific aims will be pursued:

Aim 1: To determine if ER α in male hindbrain neurons is required and/or sufficient for the control of energy homeostasis. Deletion mice, or mice with ER α re-expressed in hindbrain at null background, will be used to examine the necessity and sufficiency of hindbrain ER α for regulation of energy homeostasis in males.

Aim 2: To determine if ER α in male Phox2b neurons is required for the postnatal programming of energy homeostasis. Effects of ER α on development of hindbrain feeding circuits will be examined. Metabolic profile will be characterized in male deletion mice, which are exposed to a high- or low-phytoestrogen diet.

Aim 3: To determine if aromatase-originated estradiol is required for ER α in Phox2b neurons to regulate energy balance. Metabolic phenotypes will be characterized in male deletion mice at aromatase null versus wildtype background.

We will also determine whether aromatase-expressing cells are located in or project to the hindbrain and whether aromatase activity is regulated by gender, age and nutrition status.

These experiments may reveal novel mechanisms underlying metabolic benefits of estrogen in males and provide experimental basis for application of estrogen and its analogs to treat obesity and diabetes in men.

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

Obesity is a major risk factor for type II diabetes and increased understanding of body weight regulation may lead to effective strategies to combat obesity and diabetes. The sex hormone, estrogen, plays a beneficial role in maintaining normal body weight not only in women but also in men. Although numerous investigators have been trying to determine mechanisms by which estrogen regulates energy balance in females, relatively less effort is devoted to understanding how estrogen acts in males to maintain normal body weight. Pilot studies showed that male mice lacking estrogen receptor α (ER α) in a subset of neurons (Phox2b neurons) in the brain develop obesity, while female mice with the same mutation are normal. These raise the possibility that estrogen acts on these specific neurons in the male brains to provide anti-obesity benefits. Objectives of the current grant include to determine the physiological roles of ER α expressed by Phox2b neurons in male brains in the regulation of energy balance and to evaluate the role of these ERα neurons in mediating the metabolic effects of neonatal exposure to phytoestrogens. In addition, a series of experiments are designed to explore the mechanisms underlying the anti-obesity effects of ER α in male brains and to identify the biological origin of estrogen that acts on these ERα neurons. Thus, these experiments may reveal novel mechanisms underlying the metabolic benefits of estrogen in males and may provide experimental basis for the application of estrogen and its analogs to treat obesity and diabetes in men.

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

My long standing research goals are to identify the novel neural circuits, neurotransmitters and intracellular molecules that are critical for the coordinated control of energy and glucose homeostasis and therefore to provide rational targets for developing therapeutic strategies for obesity and diabetes. I am personally committed to this research field and will devote my career to pursuing these goals.

My research training so far has been focused on using Cre-loxP mouse models, neuroanatomy, physiology, molecular endocrinology approaches to unravel the complex mechanisms in mammal brains that regulate body weight and glucose balance. The current project represents a logical extension of my previous findings that lack of ER α in Phox2b neurons causes obesity in males but not in females. Completion of these studies will establish the physiological relevance of ERα in male brains in the regulation of energy homeostasis and may provide experimental basis for the application of estrogen and its analogs to treat obesity and diabetes in men.

As a young investigator, I am at a critical stage of my career. This ADA award will provide necessary support, which otherwise will not be available, to help me establish my laboratory. Data obtained from these studies will also provide important groundwork that will guide me to create novel hypotheses competitive for R01 funding.

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

I expect a few directions the future diabetes research may go:

1. Research will involve more collaborative efforts from both basic and clinical investigators. These studies will be more translational and the transition from bench to bed will be more efficient.
2. More efforts will be focused on obesity, a major risk factor of diabetes. Especially, understanding how body weight is controlled and development of novel anti-obesity therapies represent one of the priorities of diabetes field.
3. More modern technology will be applied in the diabetes research. For instance, the use of genetic mouse models has substantially advanced our understanding about the glycemic control. Another example could be the adaptation of gastric bypass surgeries in animal models, which may lead to discovery of unknown mechanisms for the regulation of glucose and therefore facilitate development of novel anti-diabetic therapies.