It has been clear for several decades that maintenance of body weight is under genetic control, largely due to identification of mutations in mice that result in obesity. Recently, amid great excitement, several such genes have been cloned from mice and humans, and it's very likely that additional genetic determinants will soon be identified.
The incentive to understand genetic control over body weight can largely be attributed to two factors:
- Obesity is a monumental problem in the developed world and the allure of finding a drug to cure this problem is strong.
- There is a strong association between development of obesity in adulthood and development of other important diseases, including diabetes, hypertension and heart disease.
Initial Identification of "Obesity Genes"
To understand the physiology behind the "obesity genes" currently under investigation, it is valuable to first look back at some experiments conducted in the 1960's using parabiotic mice. The technique of parabiosis, which is rarely used today, involves making an incision along the lateral aspect of two animals, then suturing them together to form a parabiotic pair. The key utility of this technique is that it unites the vascular systems of the two animals, allowing exchange of blood-borne molecules.
Many years ago, geneticists identified in mice two recessive mutations which, if homozygous, led the mice to become grossly obese. The two genes were termed ob and db. Parabiotic pairs constructed between ob/ob, db/db and normal mice led to the following observations:
- Pairing an obese ob/ob mouse with a normal mouse: the ob/ob mouse lost weight
- Pairing an obese db/db mouse with a normal mouse: the normal mouse stopped eating and lost weight
- Pairing an obese ob/ob mouse with an obese db/db mouse: the ob/ob mouse stopped eating and lost weight, whereas the db/db mouse was unaffected.
- An additional experiment showed that when one of a pair of normal parabiotic mice was overfed, its "twin" lost weight.
These observations were consistent with the idea that a satiety hormone, presumably the ob gene product, is produced which binds to receptors, presumably the db gene product, in the hypothalamus and suppresses hunger.
Considerable support was recently obtained for this model by the cloning of the ob and db genes from several species. The ob gene encodes the hormone leptin and the db gene the leptin receptor. Leptin is secreted by fat cells and has dual activity of decreasing food intake and increasing metabolic rate, which makes the old "lipostatic theory" for control of food intake very appealing.
Genes Involved in Maintaining Body Weight
It is clear that leptin and its receptor are only two of what may turn out to be a large number of genes that are important genetic determinants in the control of body weight and pathogenesis of obesity. Some of the other genes and gene products identified so far that are involved in control of food intake and body weight include:
- Neuropeptide Y is synthesized in many areas of the brain and is a potent stimulator of feeding behavior. Leptin appears to suppress feeding in part by inhibiting expression of neuropeptide Y.
- Melanocortins effect certain hypothalamic neurons and inhibit of feeding behavior. Targeted disruptions of the melanocortin-4 receptor in mice are associated with development of obesity.
- Carboxypeptidase E (fat gene) is the enzyme necessary for proteolytic processing of proinsulin and perhaps other hormones such as neuropeptide Y. Mice with mutations in this gene gradually become obese as they age, and develop hyperglycemia that can be suppressed by treatment with insulin.
- Mitochondrial uncoupling proteins were first discovered in brown fat, and subsequently identified in white fat and muscle cells. They allow mitochondria within those cells to uncouple oxidative phosphorylation, which "short circuits" the proton gradient across the inner membrane, leading to diminished production of ATP, but generating heat (nonshivering thermiogenesis). Some research suggests that they may play an important role in energy expenditure and thus body weight in man and other non-hybernating animals.
- Beta-adrenergic receptors are present on brown fat and perhaps white fat. Binding of norepinephrine to this receptor on fat cells leads to increased transcription of the mitochondrial uncoupling protein, allowing increased heat production via hydrolysis of fatty acids. It was recently reported that certain mutations in this gene predisposed people to become obese and develop diabetes before middle age.
- Tubby protein, along with tubby-related proteins, are presumed transcription factors. Tubby protein is highly expressed the paraventricular nucleus of the hypothalamus and other regions of the brain. Mice with naturally-occurring or engineered mutations in the tubby gene show adult onset of obesity, but the mechanisms involved are not known.
References and Reviews
- Comuzzie AG and Allison DB: The search for human obesity genes. Science 280:1374, 1998.
- Gura T: Uncoupling proteins provide new clue to obesity's causes. Science 280:1369, 1998.
- Martin RJ, White BD, Hulsey MG: The regulation of body weight. Amer Scientist 79:528-541, 1991. [review of parabiosis experiments and control of food intake in general]
- Naggart JK, Fricker LD, Varlomov O, etc: Hyperproinsulinemica in obese fat/fat mice associated with a carboxypeptidase E mutation which reduces enzyme activity.
- Santagata S, Boggon TJ, Baird CL, etc: G-protein signaling through tubby proteins. Science 292:2041-2050, 2001.
- Wolf G: A new uncoupling protein: a potential component of the human body weight regulation system. Nutrition Reviews. 55:178, 1997.
- Woods SC, Seeley RJ, Porte D, Schwartz MW: Signals that regulate food intake and energy homeostasis. Science 280:1378, 1998.