The observations reported here that EP3R–/– mice have an obese phenotype include measurements of body weight, as well as endocrine parameters known to increase with obesity, such as insulin and leptin plasma levels. Although it has been reported that PGE2 stimulates leptin release from adipocytes (52), we show that the lack of EP3R signaling in EP3R–/– mice does not prevent the large increase in leptin levels (Fig. 2 Lower), which is commensurate with the increased fat deposits (Fig. 1C). Thus, PGE2 stimulation of leptin release does not exclusively depend on signaling through the EP3 prostanoid receptor subtype.
The levels of PGE2 in obese humans are elevated (56). It will be interesting to test the hypothesis that such elevation could be attributable to disruption of PGE2-negative feedback through EP3R.
EP3R receptors are broadly expressed in the periphery and in the brain. Our study did not determine the site(s) of action that contributes to the obese phenotype of EP3R–/– mice, because both peripheral and central expression of EP3R is absent in the null mouse. The exact localization of the prostanoid receptor(s)-mediated febrile effects by transgenic and lentiviral techniques is currently being studied by Lazarus (57), and similar techniques will be needed to precisely determine the site(s) at which the lack of PGE2 signaling via EP3R contributes to this obese phenotype. Although it is possible to speculate that obesity in EP3R–/– mice may be caused in part by the lack of hypothalamic PGE2 signaling, numerous peripheral actions of PGE2 are also mediated through this prostanoid receptor subtype (34).
The finding of increased feeding coupled with nocturnal motor activity in EP3R–/– mice compared with WT littermates suggests that EP3R–/– mice do not stabilize sleep and may wake up more easily. The role of PGE2 as a somnogenic agent alongside prostaglandin D in sleep has been reported (45). Our data suggest that EP3R may actually mediate a part of this response.
The most likely brain–EP3R-linked response is the febrile response. It has been shown that EP3R–/– mice do not mount fever in response to the pyrogens IL-1
and LPS, suggesting that the PGE2 action in the anterior hypothalamus, raphe pallidus, and other sites involved in the generation of the fever response involves EP3R (5). The basal temperature regulation may also involve EP3R-mediated effects of PGE2, and we observed a slightly elevated core body temperature in freely moving ad libitum-fed EP3R–/– mice. The increased core body temperature and motor activity would be predicted to lead to a decrease in body weight because energy demands are increased when higher body temperature needs to be maintained, but it appears as though the increase in food consumption/energy intake has a more pronounced effect, thus resulting in body weight gain.
The onset of obesity does not occur late in development in EP3R–/– mice and does not seem to require additional age-dependent factors to come into play. It is important to note that the obesity in EP3R–/– mice does not result from the high-fat diet that is now commonly used to achieve an obese state in experimental animals; rather, this obesity in EP3R–/– mice occurs on standard chow and results from increased feeding in the absence of a commensurate increase in energy expenditure. This increase in energy intake relative to energy expenditure is often deemed to be an important factor in the etiology of common forms of human obesity. In addition, it is worth noting that EP3R–/– mice show another common feature of weight-gain scenarios in humans: night eating.
It is important to note that the lack of the full spectrum of inflammatory signaling has been shown recently to lead to obesity in a multitude of transgenic models including IL-1R1–/– (58), IL-1–/–/IL-6–/– double knockout (59), and IL-18–/– (60) mice. These observations, together with those in the EP3R–/– mice described here, suggest that inflammatory molecules and/or signaling may be required for keeping body weight homeostasis. The exact mechanism leading to obesity in these models is not known, although effects of cytokines on insulin resistance and insulin receptor substrate expression (61) and phosphorylation have been proposed (62). It will be important to determine whether those mechanisms are distinct or similar to those leading to obesity in EP3R–/– mice. Full pharmacological characterization of the contribution of EP3 mediated-signaling in obesity and other phenotypes awaits the introduction of an EP3 prostanoid receptor-specific antagonist, in the same manner that EP1 antagonist-medicated impulsive behavior served to verify the involvement of that receptor subtype in the behavioral effects (63).
In summary, mice that are null for the prostanoid receptor EP3 display increased feeding throughout the day along with additional feeding activity peaks during the night (or light period), resulting in obesity. These mice may represent an important obesity model.
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