The hormonal factors associated with converting a corpus luteum of estrous cycle into a corpus luteum of pseudopregnancy were studied by measuring LH and FSH prolactin, estradiol and progesterone levels in decapitated rats during the 4-day estrous cycle and a comparable time of pseudopregnancy (lights on 0600-0800 hr.). During the estrous cycle, prolactin, LH and FSH remained low and unchanging except on the afternoon of proestrus, when typical proestrous surges were observed. In contrast, estradiol levels began to increase on D-1, from baseline values of 7 pg/ml to approximately 15-20 pg/ml. These levels were maintained until the afternoon of D-2 when estradiol further increased to reach peak levels of 40-50 pg/ml by 0900 hr on proestrus. Estradiol then declined in relation to the increase in LH secreation and had returned to baseline by estrus. Progesterone secretion by the corpora lutea of the cycle also increased on the afternoon of D-1 and reached a maximum value of 25-30 ng/ml early on the morning of D-2. At this time, a precipitious fall in progesterone occurred, returning to baseline values of 5-1- ng/ml by 0700 on D-2 signifying the regression of the corpora lutea of the cycle. Progesterone remained low thereafter until the afternoon of proestrus when levels increased in response to the proestrus when levels increased in response to the proestrous surge of LH. Following cervical stimulation at 1900 hr on proestrus, no differences were noted, with respect to the estrous cycle, in LH, FSH or estradiol secreation through the afternoon of D-2. Surprisingly, progesterone levels did not differ in the cycle and pseudopregnancy until the early morning of D-29 instead of progesterone levels falling to baseline as they had during the cycle, the corpora lutea of pseudopregnancy were rescused, progesterone increasing dramatically to reach levels of 45-50 ng/ml by 1700 hr on that same day. The only difference in hormone secretion that was noted which could account for this marked divergence in progesterone secretion was the pattern of prolactin secretion following cervical stimulation. In contrast to the low levels seen during the estrous cycle, biphasio surges of prolactin secretion occured each day, one being nocturnal (0100-0900 hr) and the other diurnal (1500-2100 hr). The rescue of the corpus luteum occured in association with the nocturnal surge on D-2. These results suggest that nocturnal surge on D-2, PROLACTIN IS THE MAJOR Luteotropic stimulus which transforms and estrous cycle into pseudopregnancy by prolonging progesterone secretion from the corpus luteum. Moreover, if LH is important for progesterone secretion, no changes were observed in the pattern of LH secretion which can account for the rescue of the corpus luteum.

Maternal obesity is thought to increase the offspring's risk of juvenile obesity and metabolic diseases; however, the mechanism(s) whereby excess maternal nutrition affects fetal development remain poorly understood. Here, we investigated in nonhuman primates the effect of chronic high-fat diet (HFD) on the development of fetal metabolic systems. We found that fetal offspring from both lean and obese mothers chronically consuming a HFD had a 3-fold increase in liver triglycerides (TGs). In addition, fetal offspring from HFD-fed mothers (O-HFD) showed increased evidence of hepatic oxidative stress early in the third trimester, consistent with the development of nonalcoholic fatty liver disease (NAFLD). O-HFD animals also exhibited elevated hepatic expression of gluconeogenic enzymes and transcription factors. Furthermore, fetal glycerol levels were 2-fold higher in O-HFD animals than in control fetal offspring and correlated with maternal levels. The increased fetal hepatic TG levels persisted at P180, concurrent with a 2-fold increase in percent body fat. Importantly, reversing the maternal HFD to a low-fat diet during a subsequent pregnancy improved fetal hepatic TG levels and partially normalized gluconeogenic enzyme expression, without changing maternal body weight. These results suggest that a developing fetus is highly vulnerable to excess lipids, independent of maternal diabetes and/or obesity, and that exposure to this may increase the risk of pediatric NAFLD.

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Childhood obesity is associated with increased risk of behavioral/psychological disorders including depression, anxiety, poor learning, and attention deficient disorder. As the majority of women of child-bearing age are overweight or obese and consume a diet high in dietary fat, it is critical to examine the consequences of maternal overnutrition on the development of brain circuitry that regulates offspring behavior. Using a nonhuman primate model of diet-induced obesity, we found that maternal high-fat diet (HFD) consumption caused perturbations in the central serotonergic system of fetal offspring. In addition, female infants from HFD-fed mothers exhibited increased anxiety in response to threatening novel objects. These findings have important clinical implications as they demonstrate that exposure to maternal HFD consumption during gestation, independent of obesity, increases the risk of developing behavioral disorders such as anxiety.

The ability of luteinizing hormone-releasing hormone (LHRH) neurons to express the oncogene c-fos was examined during the estrous cycle in rats. The immunocytochemical localization of the c-fos-encoded antigen, Fos, was coupled with the immunocytochemical localization of LHRH.LHRH neurons showed no Fos immunoreactivity during diestrus-1, diestrus-2, estrus, or the morning of proestrus. However, Fos was expressed in LHRH neurons from 1600 to 2200 hours during proestrus. (4,5), is increased at the time of the LH surge but not at other times during the estrous cycle. While it is tempting to associate increased output of LHRH during the estrous cycle with increased stimulation of LHRH cells, direct evidence is lacking. The ability of various neurotransmitters to effect LHRH release from the median eminence or from synaptosome preparations (6-8), both of which lack LHRH soma, raises the question of the site of LHRH activation during an LH surge.Direct evidence for activation of LHRH neurons at their perikarya at the time of an LH surge has come from the MATERIALS AND METHODS Animals. Adult female Sprague-Dawley rats were maintained on a 12 hr light/12 hr dark schedule (lights on 0600-1800) and given free access to food and water. All rats showed two or more consecutive 4-day estrous cycles (by daily vaginal smear) before sacrifice. At designated times during the estrous cycle (Table 1) representing defined stages of LH secretion, rats were killed by an overdose of pentobarbital and prepared for immunocytochemical localization of Fos and LHRH (20).Pentobarbital prevents the LH surge when administered prior to the anticipated LH surge on proestrus (22). On the day following pentobarbital anesthesia, animals will manifest a delayed LH surge at the same time of day that the normal LH surge would have appeared. To study the effect of pentobarbital on Fos expression in LHRH neurons, seven animals were given pentobarbital (75 mg/kg, i.p.) at 1230 on proestrus to block the preovulatory LH surge. Four of these animals were killed between 1600 and 1630 on the day of pentobarbital treatment and the three remaining animals were killed between 1600 and 1630 on the following day, at the time of the anticipated delayed LH surge.Immunocytochemical Procedures. Rats were killed by an overdose of pentobarbital (100 mg/kg, i.p.) and perfused transcardially, first with normal saline (0.9% NaCl) containing 2% sodium nitrite and then with 2.5% acrolein (EM grade, Polysciences) in phosphate-buffered 4% paraformaldehyde Abbreviations: LH, luteinizing hormone; LHRH, LH-releasing hormone; OVLT, organum vasculosum of the lamina terminalis. *To whom reprint requests should be addressed. 5163The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

The hypothalamic melanocortin system, which controls appetite and energy expenditure, develops during the third trimester in primates. Thus, maternal nutrition and health may have a profound influence on the development of this system. To study the effects of chronic maternal high-fat diet (HFD) on the development of the melanocortin system in the fetal nonhuman primate, we placed adult female macaques on either a control (CTR) diet or a HFD for up to 4 yr. A subgroup of adult female HFD animals was also switched to CTR diet during the fifth year of the study (diet reversal). Third-trimester fetuses from mothers on HFD showed increases in proopiomelanocortin mRNA expression, whereas agouti-related protein mRNA and peptide levels were decreased in comparison with CTR fetuses. Proinflammatory cytokines, including IL-1beta and IL-1 type 1 receptor, and markers of activated microglia were elevated in the hypothalamus, suggesting an activation of the local inflammatory response. Fetuses of diet-reversal mothers had normal melanocortin levels. These results raise the concern that chronic consumption of a HFD during pregnancy, independent of maternal obesity and diabetes, can lead to widespread activation of proinflammatory cytokines that may alter the development of the melanocortin system. The abnormalities in the fetal POMC system, if maintained into the postnatal period, could impact several systems, including body weight homeostasis, stress responses, and cardiovascular function. Indeed, the HFD offspring develop early-onset excess weight gain. These abnormalities may be prevented by healthful nutrient consumption during pregnancy even in obese and severely insulin-resistant individuals.

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