International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)

F5. Understanding Body Weight Regulation with Genetics and Gene Expression Profiling

Karine Clement1, Sophie Candille1, Yasushi Okazaki2, Yoshihide Hayashizaki2, and Greg Barsh1
1Depts. of Pediatrics and Genetics and HHMI, Stanford University School of Medicine, Stanford, CA 94305, US;
Genomic Sciences Center, The Institute of Physical and Chemical Research (RIKEN) 3-1-1 Koyadai, Tsukuba, Ibaraki 305, Japan.

Molecular studies of the ob and Ay mutations have provided remarkable insight over the last decade into mechanisms that balance energy intake with energy expenditure. Leptin is the afferent arm of a homeostatic circuit in which neuropeptides produced in the hypothalamus act via the Melanocortin 4 receptor (Mc4r) to initiate compensatory responses to energy deprivation (leptin and/or caloric deficiency) or energy excess. Leptin-deficiency (in ob/ob mice) and Mc4r blockade (in Ay mice) both cause obesity but in very different patterns: Ay mice develop overgrowth and have a relatively mild hypercortisolism whereas ob/ob mice develop a reduction in lean body mass and exhibit profound disturbances of the thyroid, reproductive, and HPA axes.

To better understand the difference between these phenotypes and the relationships between the leptin and central melanocortinergic pathways we have measured patterns of gene expression in non-mutant, ob/ob, and Ay mutant mice, either free-fed or fasted for 48 hours. Gene expression profiles were determined using spotted arrays of mouse cDNAs from Phase I of the Mouse Encyclopedia, and analyzed with hierarchical clustering. Of approximately 16,000 genes queried, 900 exhibited changes greater than 2-fold across the entire data set. In peripheral tissues of normal mice, fasting induces profound changes in gene expression in which distinct metabolic pathways can be identified including fatty acid biosynthesis, oxidative phosphorylation, and protein catabolism.

Gene expression patterns in ob/ob mice are nearly identical to fasted non-mutant mice, whereas gene expression patterns in Aymice are nearly identical to free-fed non-mutant mice. Thus, the difference between the mutant phenotypes is most easily explained by changes in energy balance perception: Ay animals fail to respond to starvation whereas ob/ob behave as though they are starving even when they are not. Because the patterns of gene expression are not affected by fasting in either mutant, signals emanating from the leptin or the melanocortinergic systems can override the actual state of energy balance.

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