The aromatase-knockout (ArKO) mouse provides a useful model to examine the role that estrogens play in development and homeostasis in mammals. Lacking a functional Cyp19 gene, which encodes aromatase, the ArKO mouse cannot synthesize endogenous estrogens. We examined the adipose depots of male and female ArKO mice, observing that these animals progressively accumulate significantly more intraabdominal adipose tissue than their wild-type (WT) littermates, reflected in increased adipocyte volume at gonadal and infrarenal sites. This increased adiposity was not due to hyperphagia or reduced resting energy expenditure, but was associated with reduced spontaneous physical activity levels, reduced glucose oxidation, and a decrease in lean body mass. Elevated circulating levels of leptin and cholesterol were present in 1-year-old ArKO mice compared with WT controls, as were elevated insulin levels, although blood glucose levels were unchanged. Associated with these changes, a striking accumulation of lipid droplets was observed in the livers of ArKO animals. Our findings demonstrate an important role for estrogen in the maintenance of lipid homeostasis in both males and females.

https://www.pnas.org/content/pnas/97/23/12735.full.pdf

Aromatase-deficient (ArKO) mice have a phenotype of increased adiposity

Metabolic fuels and reproduction in female mammals.

Several sex differences in eating, their control by gonadal steroid hormones and their peripheral and central mediating mechanisms are reviewed. Adult female rats and mice as well as women eat less during the peri-ovulatory phase of the ovarian cycle (estrus in rats and mice) than other phases, an effect under the control of cyclic changes in estradiol secretion. Women also appear to eat more sweets during the luteal phase of the cycle than other phases, possibly due to simultaneous increases in estradiol and progesterone. In rats and mice, gonadectomy reveals further sex differences: orchiectomy decreases food intake by decreasing meal frequency and ovariectomy increases food intake by increasing meal size. These changes are reversed by testosterone and estradiol treatment, respectively. A variety of peripheral feedback controls of eating, including ghrelin, cholecystokinin (CCK), glucagon, hepatic fatty acid oxidation, insulin and leptin, has been shown to be estradiol-sensitive under at least some conditions and may mediate the estrogenic inhibition of eating. Of these, most progress has been made in the case of CCK. Neurons expressing estrogen receptor-α in the nucleus tractus solitarius of the brainstem appear to increase their sensitivity to CCK-induced vagal afferent input so as to lead to an increase in the satiating potency of CCK, and consequently decreased food intake, during the peri-ovulatory period in rats. Central serotonergic mechanisms also appear to be part of the effect of estradiol on eating. The physiological roles of other peripheral feedback controls of eating and their central mediators remain to be established.

/pdf/modulation-of-appetite-by-gonadal-steroid-hormones-3zry7aa1jj.pdf

Modulation of appetite by gonadal steroid hormones

Gonadal effects on food intake and adiposity: a metabolic hypothesis.

IT is now well established that progesterone can either facilitate or inhibit the effects of oestrogen on gonadotrophin release and behaviour1. Whether facilitation or inhibition is observed depends primarily on the time interval between exposure to oestrogen and progesterone, but the mechanism by which progesterone exerts these effects remains unknown. Attempts to demonstrate progesterone receptor sites within the brain and pituitary have given equivocal results2–10, leading to speculation that the central effects of progesterone may be mediated through a mechanism fundamentally different from that found in peripheral tissues1,2,6. More recently, however, several studies have suggested that oestrogen-inducible progestin receptor systems similar to those found in peripheral progesterone target tissues can be identified in the brain and pituitary if sufficiently sensitive and specific experimental procedures are used11–14. We summarise here work from our laboratory which indicates that, in the rat brain, there are in fact two anatomically distinct progestin receptor systems, one of which differs strikingly from the systems identified previously in neural and non-neural tissues in that it is apparently insensitive to oestrogen.

Oestrogen modulates progestin receptor concentrations in some rat brain regions but not in others

Gonadal hormones and behavioral regulation of body weight

[1,2-3H]progesterone uptake by guinea pig brain and uterus: Differential localization, time-course of uptake and metabolism, and effects of age, sex, estrogen-priming and competing steriods

Uptake of [6,7-3H]Estradiol-17β in ovariectomized rats, guinea pigs, and hamsters: Correlation with species differences in behavioral responsiveness to estradiol

Neural uptake of (1,2-3H)progesterone in ovariectomized rats, guinea pigs and hamsters: correlation with species differences in behavioral responsiveness.

George N. Wade

Papers

Gonadal hormones and behavioral regulation of body weight

[1,2-3H]progesterone uptake by guinea pig brain and uterus: Differential localization, time-course of uptake and metabolism, and effects of age, sex, estrogen-priming and competing steriods

Uptake of [6,7-3H]Estradiol-17β in ovariectomized rats, guinea pigs, and hamsters: Correlation with species differences in behavioral responsiveness to estradiol

Neural uptake of (1,2-3H)progesterone in ovariectomized rats, guinea pigs and hamsters: correlation with species differences in behavioral responsiveness.

Effects of several pregnane and pregnene steroids on estrous behavior in ovariectomized, estrogen-primed guinea pigs.