Neuropeptide Y gene expression in lines of mice subjected to long-term divergent selection on fat content.

Lines of mice have been developed in our laboratory by divergent long-term selection for body fat content. This has resulted in a fivefold (23% vs 4%) higher fat percentage in the Fat line at 14 weeks of age, with little difference between the Fat and Lean lines in fat-free body weight. As part of an approach to characterize the physiological mechanisms underlying these different phenotypes, neuropeptide Y (NPY) mRNA levels in the hypothalamus and cerebral cortex of ad libitum-fed and fasted mice of the Fat and Lean selected lines were measured. Significant differences in NPY gene expression were confined to the hypothalamus. Under ad libitum-fed conditions, hypothalamic NPY mRNA levels did not differ significantly between the Fat and Lean lines. After an overnight fast of 18-20 h, hypothalamic NPY mRNA levels were increased significantly (P<0.05) by 31% in Lean animals relative to fed mice from the same line. However, fasting did not significantly stimulate NPY gene expression in the Fat line. Most plasma leptin measurements in the Lean line fell below the sensitivity threshold of the assay (0.1 ng/ml), but levels in the Fat line were at least 30 to 50 times higher under fasted and fed conditions respectively. After fasting, plasma leptin levels in the Fat line decreased significantly (P<0. 05) by 48%. Thus, unlike the situation in other rodent models, obesity in the Fat line is not associated with increased hypothalamic NPY mRNA levels in the ad libitum-fed state. The decreased sensitivity of hypothalamic NPY gene expression to fasting in the Fat line is consistent with an inhibitory effect of higher circulating leptin levels.