Obesity and Overeating

Research Fundamentals

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• Publisher: Wiley-Blackwell
• Year: 2013
• ISBN:
  9781118734292
• Edition: 1
• Topic: Medicine
• Subtopic: Endocrinology & Metabolism

With the increasing worldwide incidence of obesity and the resulting increase in metabolic disorders such as diabetes, cardiovascular diseases and some cancers, an understanding of the multitude of factors that contribute to obesity is crucial for researchers to develop more effective treatments. This collection of overviews and protocols provides the reader with an introduction to the major features of obesity research, including the interplay between energy balance, hormones and neurobiological networks. An overview is provided which describes the animal models of obesity most commonly utilized in research. A standardized laboratory protocol for producing diet?]induced obesity (DIO) in both mouse and rat is provided as are protocols that describe how diet formulation can be modified to generate mouse models of human metabolic pathologies. Protocols are also provided for testing the effects of dietary manipulations, caloric restriction and potential therapeutics.

This e-book — a curated collection from eLS, WIREs, and Current Protocols — offers a fantastic introduction to the field of obesity research for students or interdisciplinary collaborators.

John Wiley & Sons, Ltd.

Current Protocols in Pharmacology 5.61.1-5.61.18, September 2012

Published online September 2012 in Wiley Online Library (wileyonlinelibrary.com).

DOI: 10.1002/0471141755.ph0561s58

Copyright © 2012 John Wiley & Sons, Inc.

UNIT 5.61

Overview of Animal Models of Obesity

Thomas A. Lutz¹ and Stephen C. Woods²

¹University of Zurich, Institute of Veterinary Physiology, Zurich Center of Integrative Human Physiology, Zurich, Switzerland

²Department of Psychiatry and Behavioral Neuroscience, College of Medicine, University of Cincinnati Obesity Research Center, Cincinnati, Ohio

ABSTRACT

The focus of this overview is on the animal models of obesity most commonly utilized in research. The models include monogenic models in the leptin pathway, polygenic diet-dependent models, and, in particular for their historical perspective, surgical and chemical models of obesity. However, there are far too many models to consider all of them comprehensively, especially those caused by selective molecular genetic approaches modifying one or more genes in specific populations of cells. Further, the generation and use of inducible transgenic animals (induced knock-out or knock-in) is not covered, even though they often carry significant advantages compared to traditional transgenic animals, e.g., influences of the genetic modification during the development of the animals can be minimized. The number of these animal models is simply too large to be covered in this unit. Curr. Protoc. Pharmacol. 58:5.61.1-5.61.18. © 2012 by John Wiley & Sons, Inc.

Keywords: monogenic models • polygenic models • genetic engineering • surgical model • leptin • diabetes • hyperglycemia

INTRODUCTION

The incidence of obesity continues to climb worldwide, making it imperative that animal models sharing characteristics of human obesity and its co-morbidities be developed in the quest for novel preventions and/or treatments. While there is a clear and well-documented genetic component for the tendency to become obese, most instances of human obesity are nonetheless considered to be polygenic, resulting from the integrated activity of numerous genes, each of which carries only a small risk factor. Animal models of obesity can therefore be partitioned into different categories, the major ones being based on mutations or manipulations of one or a few individual genes versus those in genetically intact animals exposed to obesigenic environments such as being maintained on high-fat diets.

While it is beyond the scope of this overview to delve into the causes of obesity, many excellent reviews exist (Schwartz et al., 2003; Leibel, 2008; Woods, 2009; Kaiyala and Schwartz, 2011). Considerable research is based on the premise that a primary causal factor lies in the interaction of the brain with peripheral tissues such as the gut, the liver, the endocrine pancreas, adipose tissue, and others. This is typically manifested as dysfunctional eating, energy metabolism, and/or autonomic activity. Note that this could occur via abnormal signaling by peripheral organs to the brain (e.g., indicating that insufficient fat is present, thus triggering increased food intake and consequent increased body fat) and/or by abnormal signaling from the brain to other organs (e.g., reduced sympathetic and increased parasympathetic activity to the endocrine pancreas and liver after certain brain lesions).

Because food intake has high face validity when considering possible factors influencing body adiposity, most characterizations of animal models include assessments of intake as well as of body fat, plasma leptin, insulin, and glucose, and other related parameters. It is therefore important to understand the basics of the control of food intake and how they might relate to obesity. It is generally accepted that factors that influence food intake and consequently body fat can be conceptualized as those that influence when individuals start eating and those that influence when eating, once begun, will end: i.e., factors that stimulate appetite or eating per se and those that signal fullness or satiation. Except in rare circumstances, eating is initiated by factors such as habit, time of day, the social situation, food availability, and so on (Woods, 1991, 2009). The amount eaten (i.e., meal size), on the other hand, is determined by satiation factors generated by the gastrointestinal system interacting with ingested food. The best known satiation factor is the intestinal peptide cholecystokinin (CCK). Satiation factors interact in the brain with signals emanating from adipose tissue and other organs indicating how lean or fat the individual is. These adiposity signals, such as leptin and insulin, interact with receptors in the hypothalamus and have potent effects on food intake, energy expenditure, and the level of stored fat. The majority of animal models commonly used to investigate causes and treatments for obesity therefore have altered activity in brain circuits integrating satiation and adiposity signals (Woods, 1991, 2009).

ANIMAL MODELS OF OBESITY

Admittedly, reviews of animal models of obesity are always somewhat subjective for the choice of models included. The criteria for choosing the animal models described in this unit (Table 5.61.1) were:

• The model has been used frequently in obesity research.
• The model has a historic perspective, e.g., it enabled identification of major areas in the brain involved in the control of eating and body weight.
• The model has been influential for the subsequent generation of more specific animal models, e.g., specific knockout or transgenic (potentially inducible) models based on the discovery of the leptin pathway.
• The models cover the most important different types of models such as genetic or nongenetic models.
• Within the genetic models, monogenic and polygenic models are represented.
• Within monogenic models, two main categories are represented—monogenic models linked to the pathway of an adiposity signal (undoubtedly, the leptin pathway was the most critical to trigger an enormous research activity in recent years) and of a satiation signal like CCK.
• The animal model shows a distinct phenotype of obesity, hyperphagia, or change in energy metabolism.
• The animal model may also show some of the most frequent comorbidities of obesity, like hyperglycemia, insulin resistance, or diabetes-like syndromes.

Table 5.61.1 Summary of Animal Models of Obesity Described in this Unit^a

Because it is the best understood, the first models discussed concern monogenic (single-gene) mutations involving the leptin pathway (Schwartz et al., 2000). Spontaneous mutations leading to marked obesity had been described long before the underlying causes (e.g., defects in the leptin gene or the leptin receptor gene) had been discovered. Discoveries in this pathway led to the subsequent generation of a large number of engineered mutants. Another prominent animal model of obesity that resulted from a spontaneous mutation is the Otsuka Long Evans Tokushima Fatty (OLETF) rat, which lacks functional receptors for the satiating hormone CCK. Diet-induced models of obesity (DIO) are often used to study polygenic causes of obesity. DIO animals are believed to better mimic the state of common obesity in humans than most of the genetically modified models, and may be the best choice for testing prospective therapeutics. Finally, models of surgically or chemically induced and seasonal models of obesity are summarized. Surgically induced obesity has lost much of its importance since the introduction of genetically modified animals, which allow the more specific ablation of neurons in defined parts of the brain.

Most animal models of obesity are small rodents (rats or mice), but it should be mentioned that most mammals, when maintained in small enclosures with free food (as in many zoos in the past), develop obesity. The most commonly used animal models of obesity are probably the leptin-deficient ob/ob mouse, the leptin receptor deficient db/db mouse, its rat counterparts like the Zucker rat, the MC4 receptor-deficient animals and models of diet-induced obesity.

The choice of model for a particular experiment depends upon the goal of the study. For example, as described above, DIO animals may be the best choice for testing prospective therapeutics. Transgenic models or models with spontaneous mutations may be used in the evaluation of a prospective therapeutic to determine whether it engages a specific target or pathway in vivo. The transgenic models and models with spontaneous mutations may also be used to explore the role of specific molecular targets and pathways in the physiology of food intake and their potential role in obesity.

MONOGENIC MODELS: MONOGENIC MUTATIONS IN THE LEPTIN PATHWAY

Leptin and Its Receptor

Animals with a defect in the leptin-signaling pathway in the hypothalamus of the brain develop a morbidly obese phenotype. The models include animals that lack leptin production and/or that are insensitive to leptin due to leptin receptor mutations or extreme leptin resistance. Mutations are spontaneous (e.g., Lep^ob/Lep^ob mouse; Lep^db/Lep^db mouse) or genetically engineered. Animals with mutations that lie downstream of the leptin-sensing neurons in the hypothalamus are also included.

ob/ob mouse (Lep^ob/Lep^ob mouse, the ‘obese’ mouse)

A spontaneous mutation leading to the markedly obese phenotype in the Lep^ob/Lep^ob mouse has been recognized since the 1950s (Mayer et al., 1951; Coleman, 1978). However, it was not until the discovery in 1994 of the underlying mechanisms and characterization of the ob gene product, leptin, that intensive research on the genetics of obesity increased dramatically (Zhang et al., 1994). Today, the ob gene is one of the most studied genes in obesity research. A single-base spontaneous mutation of the ob gene prevents the secretion of bioactive leptin because leptin synthesis is terminated prematurely. Leptin is mainly synthesized in white adipocytes, and its secretion is directly proportional to the amount of stored triglyceride. Leptin deficiency has also been observed in rare cases of human obesity (O’Rahilly, 2009).

Phenotypically, the lack of leptin leads to marked, early-onset obesity characterized by hyperphagia, reduced energy expenditure, and hypothermia; further defects are hypercorticosteronemia, insulin resistance associated with hyperglycemia and hyperinsulinemia, hypothyroidism, and growth hormone deficiency leading to a decrease in linear growth. Lep^ob/Lep^ob mice are infertile. Obesity in Lep^ob/Lep^ob mice is one of the few forms of obesity that can be treated effectively by the admin...

Table of contents

• Cover
• Introduction
• Primary Hormones and Receptors Studied in Obesity Research
• Protocols
• Further Reading