Nutrition and Metabolism
Section Leader
Margot P. Cleary, Ph.D. Professor

The Hormel Institute - Margot Cleary

 

Primary interests of the Nutrition and Metabolism section are the effects of body weight and food intake on the development of breast cancer using mouse models. Past studies have included effects of genetic and dietary induced obesity on breast/ mammary tumor development, particularly with respect to body fat and serum IGF-I, leptin and adiponectin levels. Other studies have assessed the effect of calorie restriction on the prevention of mammary tumors in several mouse models of breast cancer. Of particular interest, we consistently find that periods of moderately severe calorie restriction followed by refeeding . which we term .intermittent calorie restriction. . results in much greater reduction in mammary tumor incidence than the same degree of restriction implemented chronically with both interventions resulting in 20 to 25 percent calorie reduction. Mechanisms of the protective effect of caloric restriction on cancer development include studies of leptin/leptin receptors, adiponectin/adiponectin receptors, and the IGFaxis. Based on results of our studies, we hypothesized that the altered (i.e. reduced) adiponectin:leptin ratio that is characteristic of obesity provides a permissive environment for tumor development. In contrast, the reductions of IGF-I and leptin and increased adiponectin:leptin ratio resulting from intermittent calorie restriction result in decreased mammary tumor incidence in comparison to ad libitum feeding as well as to chronic calorie restriction. These studies have been expanded by Dr. Michael Grossmann of The Hormel Institute to include the interaction of an omega-3 fatty acid in combination with intermittent calorie restriction on the development of mammary tumors. Intermittent calorie restriction might provide an easier approach for individuals to reduce caloric intake for disease prevention. In fact, several recently promoted weight-loss programs utilize this approach.

The Hormel Institute - Margot Cleary Lab

Although calorie restriction has an incredible effect on cancer prevention in many rodent models, the practical aspects of implementing and maintaining this intervention in human populations has not been successful. This has led to interest in identifying compounds that act like calorie restriction, such as calorierestriction mimetics. One such compound is metformin, a commonly used type 2 diabetic drug. Our most recent work focuses on directly comparing moderate calorie restriction (25 percent reduction) to metformin treatment on the prevention of mammary tumors. This study is being conducted in a transgenic mouse model to mimic post-menopausal breast cancer and includes obese- as well as normal-weight subjects. The intervention was started when the mice were middle-age to reflect also what would occur in at-risk women. We also are conducting studies related to metformin.s effects on cancer progression. We have completed this long-term study, following the mice until they were 90 weeks of age. We did not find that metformin had a cancer-preventing effect in either lean or obese mice. NEEDS MORE TEXT/EDITING In contrast, 25 percent calorie restriction resulted With respect to mechanisms of action of these interventions not only are we assessing alterations in the AMPK pathway but also on aspects of altered glucose metabolism that may result. We anticipate our ongoing studies will provide valuable insights into ways to prevent mammary tumor development and slow disease progression. In contrast 25% calorie restriction resulted in a significant decrease in mammary tumor incidence and delayed age when tumors were detected.

The Hormel Institute - Margot Cleary Lab

(Left to right) Nancy Mizuno, DaQing Yang, Xi Pan, Ben Harris, Margot Cleary, Michael Grossmann, Brenna Nordeng
Pictured is an estrogen Not pictured: Jingfei Chen, Shuxia (Susan) Jiang, Defeng Wang

Other Professional Activities
Presentations:
Minnesota Chemoprevention Consortium, June 2015

Attended:
Obesity Week 2014, Boston, Mass., November 2014
Grant Review Committees
NIH Study Section Meetings (October 2014 and March 2015)