Figure 39.14 A Single-Gene Mutation Leads to Obesity in Mice
In the late 1960s and early 1970s, Coleman and Hummel studied the effects of parabiosis between wild-type mice and either obese (ob/ob) mice or diabetes (db/db) mice to determine if mice that become obese lack a satiety factor or a satiety factor receptor. Both strains of mutant mice used in the experiments were genetically obese, but the latter strain also had diabetes. The investigators surgically joined the circulatory systems of wild-type mice with the obese-strain mice such that the pairs could share circulating blood. The results of these experiments showed that when db/db mice were parabiosed with wild-type mice, the db/db mice did not lose weight. By comparison, when ob/ob mice were parabiosed with wild-type mice, the ob/ob mice lost weight. These results suggested a satiety factor was transmitted from the wild-type mice to the ob/ob mice, allowing them to eat less and lose weight. Together, these findings suggested that the obese gene encodes a satiety hormone, while the diabetes gene encodes a satiety receptor. Later studies supported these results and revealed that the obese gene encodes the hormone leptin and that the diabetes gene encodes the leptin receptor. In addition to leptin’s function as a satiety factor, it has also been shown to play a role in other endocrine functions, including reproduction. Studies have demonstrated that leptin levels are low in people with low body fat, and that women with low body fat often display a cessation of menstrual cycles. This effect has been attributed in part to leptin’s ability to stimulate the release of leutinizing and follicle stimulating hormones from the pituitary gland. Consistent with these findings, Clˇment and colleagues described a homozygous mutation in the human leptin receptor gene that resulted in a truncated leptin receptor. Patients homozygous for this mutation fail to achieve puberty, and their secretion of growth hormone and thyroid-stimulating hormone (TSH) is reduced. Thus, leptin appears to be involved in the regulation of several endocrine functions in humans.
Original Papers
Coleman, D. L., and K. P. Hummel. 1969. Effects of parabiosis of normal with genetically diabetic mice. American Journal of Physiology 217: 1298–1304.
D. L. Coleman. 1973. Effects of parabiosis of obese with diabetes and normal mice. Diabetologia 9: 294–297.
http://dx.doi.org/10.1007/BF01221857
See also review:
Coleman, D. L. 1978. Obese and diabetes: two mutant genes causing diabetes-obesity syndromes in mice. Diabetologia 14: 141–148.
http://dx.doi.org/10.1007/BF00429772
Clément, K., et al. 1998. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 392: 398–401.
http://dx.doi.org/10.1038/32911
See also commentary:
O'Rahilly, S. 1998. Human physiology: Life without leptin. Nature 392: 330–331.
http://dx.doi.org/10.1038/32769
Links
Friedman J. M., and J. L. Halaas. 1998. Leptin and the regulation of body weight in mammals. Nature 395: 763–770.
http://dx.doi.org/10.1038/27376
Kimball’s Biology Pages: Leptin
http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/L/Leptin.html
Colorado State University: Pathophysiology of the Digestive System: Genetics of Food Intake, Body Weight and Obesity
http://www.vivo.colostate.edu/hbooks/pathphys/digestion/pregastric/fatgenes.html
Colorado State University: Pathophysiology of the Digestive System: Leptin
http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/bodyweight/leptin.html
Chial, H., and J. Craig. 2008. Genome-wide association studies (GWAS) and obesity. Nature Education 1(1)
http://www.nature.com/scitable/topicpage/Genome-Wide-Association-Studies-GWAS-and-Obesity-752