Alan P. Jones

Maternal hormonal manipulations in rats cause obesity and increase medial hypothalamic norepinephrine release in male offspring

In previous work it has been shown that adult male, but not female, offspring of rats that have either been injected with Protamine Zinc Insulin on days 15-20 gestation, or undernourished during the first 2 weeks of gestation, develop significant obesity commencing at about 50 days of age. The present experiment examines the question of whether rats with these two forms of obesity display neurochemical abnormalities in areas of the brain known to influence food intake and body weight. Twenty-one gauge stainless steel guide shafts were surgically implanted using standard stereotaxic procedures. One week later 26 ga microdialysis probes were lowered into the medial hypothalamus. Dialysates collected from male offspring in the two experimental conditions contain significantly higher norepinephrine (NE) levels than did controls. It would appear that in addition to sharing a similar time course of onset and a sex dependent expression of obesity, both of these models are also characterized by elevated medial hypothalamic NE. Since this obesity appears only in males, and at a time when testosterone levels are rapidly rising in males, and since testosterone has been shown to elevate food intake and body weights in rats, we also investigated whether gonadal weights or circulating testosterone levels were differentially elevated by our manipulations.

The effect of diet on food intake and adiposity in rats made obese by gestational undernutrition

Undernutrition limited to the first two weeks (trimesters) of pregnancy in rats produces a delayed-onset enhancement of body weight and food intake in male but not female offspring. Adiposity measures (fat cell size, fat pad weight and carcass lipid content) however, were enhanced only in male offspring of previously deprived mothers maintained on a high-fat diet. Previous work had shown that although these adiposity differences are enhanced by this diet, hyperphagia was eliminated when animals were switched to the high-fat diet as adults. The current study demonstrates that if offspring of deprived animals are exposed to the high-fat diet early in life, hyperphagia ensues. Adipocyte number, and circulating triglyceride levels were unaffected by our nutritional manipulation.

Maternal insulin manipulations in rats organize body weight and noradrenergic innervation of the hypothalamus in gonadally intact male offspring

In previous work it has been shown that adult male, but not female, offspring of rats that have been injected with protamine zinc insulin (6 IU/kg) on days 15-20 of gestation, develop significant obesity beginning about 50 days of age. This obesity is accompanied by elevated medial hypothalamic extracellular norepinephrine levels. To examine whether the expression of obesity in male offspring is mediated by perinatal testosterone levels, male offspring of insulin-treated or control dams were either castrated or received sham surgery on postnatal day 1. Castrated male offspring of insulin-treated dams did not become obese like their gonadally intact male littermates. This suggests that perinatal testosterone levels may interact with developmental processes mediating the obesity in male offspring of insulin-treated dams. A second question addressed was whether the elevated hypothalamic extracellular norepinephrine levels observed in our earlier work are evident as morphological changes in norepinephrine-containing systems in the medial hypothalamus and locus coeruleus. We found a significant enhancement of dopamine-beta-hydroxylase immunoreactivity in fibers innervating the paraventricular nucleus of the hypothalamus in 121-day-old, gonadally intact male offspring of insulin-injected dams. This suggests that the impact of maternal insulin injections on offspring obesity may be mediated through its organizing action on feeding-related fibers in the paraventricular nucleus.

Maternal hormone manipulations and the development of obesity in rats

Pregnant rats were injected with either insulin, corticosterone, thyroxin, or saline during the third trimester (week) of pregnancy. Offspring from these groups had equivalent body weights at birth and at weaning. However, beginning at approximately seven weeks of age, male offspring in the insulin condition gained weight at significantly higher rates than their counterparts in the other three conditions. This increase in body weight was accompanied by a significant increase in carcass lipid content. These effects were not observed in female offspring.

Effects of ovariectomy on thermogenesis in brown adipose tissue and liver in Syrian hamsters

Weight gain in ovariectomized Syrian hamsters occurs without increased food intake, which suggests that metabolic efficiency may be enhanced through a reduction in energy expenditure. We examined the effect of ovariectomy on metabolic activity in brown adipose tissue and liver. Four groups of hamsters (n = 13, each) were killed 0, 2, 4, or 16 weeks following ovariectomy. Ovariectomized hamsters rapidly gained weight without overeating. Body weights stabilized after 8 weeks and remained 12-17% above sham-operated control weights for the duration of the experiment. Weight gain in the hamsters ovariectomized for 16 weeks was characterized by significant increases in retroperitoneal white adipose tissue weight and carcass lipid content. Similar trends were seen in 2-week and 4-week ovariectomized animals. There were no differences in interscapular brown adipose tissue weight, protein content, DNA content, or norepinephrine (NE) content among sham-operated and 2-, 4-, or 16-week ovariectomized hamsters, indicating that ovariectomy had no effect on brown adipose tissue growth. Similarly, there was no difference in either sympathetic nervous system activity (estimated by the rate of NE turnover) or mitochondrial GDP binding among the four groups of hamsters. In contrast, hepatic cytochrome P-450 activity was significantly reduced 2, 4, and 16 weeks after ovariectomy. These results suggest that reduced thermogenic activity in liver, but not in brown adipose tissue, could contribute to the weight gain in Syrian hamsters after ovariectomy.

OBESITY AND ADIPOCYTE ABNORMALITIES IN OFFSPRING OF RATS UNDERNOURISHED DURING PREGNANCY

Pregnant rats underfed in the first 2 weeks of gestation had offspring with normal body weight at birth and weaning. However, starting at about 5 weeks of age the male offspring became hyperphagic and gained more weight than the controls. The female offspring did not overeat and did not become obese. Both male and female progeny showed increased fat cell size as adults. In males the epididymal and retroperitoneal fat pads were significantly enlarged nd adipocytes in these pads were hypertrophied. In females and fat pads were not enlarged, but adipocytes in the parametrial pads were hypertrophied.