Abstract: International statistics indicate that there is a close correlation between the consumption of saturated fats (dairy fats and meat fats) and the mortality from coronary heart disease (CHD), and this conception has been confirmed by many epidemiological studies. Such studies alone, however, cannot prove the existence of a cause-and-effect relationship between these two variables; dietary intervention trials are needed. The Finnish Mental Hospital Study was such a trial, conducted in two hospitals near Helsinki in 1959--1971. Practically total replacement of dairy fats by vegetable oils in the diets of these hospitals was followed by a substantial reduction in the mortality of men from CHD. Total mortality also appeared to be reduced. As to the causes of death other than CHD, none was significantly influenced by dietary change. This was also true for malignant neoplasms. To alleviate the burden of CHD on public health, many investigators have recommended important changes in the quantity and quality of dietary fats.

Abstract: The maze learning ability of six pony foals that had been weaned at birth was compared to that of six foals reared normally. The foals' learning ability was also compared to their mothers' learning ability at the same task; the correct turn in a single choice point maze. The maze learning test was conducted when the foals were 6 to 8 mo old and after the mothered foals had been weaned. There was no significant difference between the ability of orphaned (weaned at birth) and mothered foals in their ability to learn to turn left (6 +/- .7 and 5.1 +/- .1 trials, respectively) or to learn the reversal, to turn right (6.7 +/- .6 and 6.2 +/- .6 trials, respectively). The orphan foals spent significantly more time in the maze in their first exposure to it than the mothered foals (184 +/- 42 vs 55 +/- 15 s. Mann Whitney U = 7, P less than .05). The mothers of the foals (n = 11) learned to turn left as rapidly as the foals (5.9 +/- .7 trials), but they were slower to learn to turn right (9.8 +/- 1.4 vs 6.4 +/- .4 trials, Mann Whitney U = 33, P less than .05), indicating that the younger horses learned more rapidly. There was no correlation between the trials to criteria of the mare and those of her foal, but there was a significant negative correlation between rank in trials to criteria and age (r = -65, P less than .05) when data from the mare and foal trials were combined. The dominance hierarchy of the mares was determined using a paired feeding test in which two horses competed for one bucket of feed. Although there was no correlation between rank in the hierarchy and maze learning ability, there was a correlation between body weight and rank in the hierarchy (r = .7, P less than .05). This may indicate either that heavier horses are likely to be dominant or that horses high in dominance gain more weight. Maternal deprivation did not appear to seriously retard learning of a simple maze by foals, although the orphans moved more slowly initially. The lack of maternal influence on learning is also reflected in the lack of correlation between the mare's learning ability and that of her foal. Young horses appear to learn more rapidly than older horses.

Abstract: Our previous study suggested that fenofibrate affects obesity and lipid metabolism in a sexually dimorphic manner in part through the differential activation of hepatic peroxisome proliferator-activated receptor alpha (PPARalpha) in male and female C57BL/6J mice. To determine whether fenofibrate reduces body weight gain and adiposity in female sham-operated (Sham) and ovariectomized (OVX) C57BL/6J mice, the effects of fenofibrate on not only body weight, white adipose tissue (WAT) mass, and food intake, but also the expression of both leptin and PPARalpha target genes were measured. Compared to their respective low-fat diet-fed controls, both Sham and OVX mice exhibited increases in body weight and WAT mass when fed a high-fat diet. Fenofibrate treatment decreased body weight gain and WAT mass in OVX, but not in Sham mice. Furthermore, fenofibrate increased the mRNA levels of PPARalpha target genes encoding peroxisomal enzymes involved in fatty acid beta-oxidation, and reduced apolipoprotein C-III (apo C-III) mRNA, all of which were expressed at higher levels in OVX compared to Sham mice. However, leptin mRNA levels were found to positively correlate with WAT mass, and food intake was not changed in either OVX or Sham mice following fenofibrate treatment. These results suggest that fenofibrate differentially regulates body weight and adiposity due in part to differences in PPARalpha activation, but not to differences in leptin production, between female OVX and Sham mice.

Abstract: Lipid-lowering fibrate drugs function as agonists for the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha). Sustained activation of PPARalpha leads to the development of liver tumors in rats and mice. However, humans appear to be resistant to the induction of peroxisome proliferation and the development of liver cancer by fibrate drugs. The molecular basis of this species difference is not known. To examine the mechanism determining species differences in peroxisome proliferator response between mice and humans, a PPARalpha-humanized mouse line was generated in which the human PPARalpha was expressed in liver under control of the tetracycline responsive regulatory system. The PPARalpha-humanized and wild-type mice responded to treatment with the potent PPARalpha ligand Wy-14643 as revealed by induction of genes encoding peroxisomal and mitochondrial fatty acid metabolizing enzymes and resultant decrease of serum triglycerides. However, surprisingly, only the wild-type mice and not the PPARalpha-humanized mice exhibited hepatocellular proliferation as revealed by elevation of cell cycle control genes, increased incorporation of 5-bromo-2'-deoxyuridine into hepatocyte nuclei, and hepatomegaly. These studies establish that following ligand activation, the PPARalpha-mediated pathways controlling lipid metabolism are independent from those controlling the cell proliferation pathways. These findings also suggest that structural differences between human and mouse PPARalpha are responsible for the differential susceptibility to the development of hepatocarcinomas observed after treatment with fibrates. The PPARalpha-humanized mice should serve as models for use in drug development and human risk assessment and to determine the mechanism of hepatocarcinogenesis of peroxisome proliferators.