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The obesity epidemic continues unabated and currently available pharmacological treatments are not sufficiently effective. Combining gut/brain peptide, GLP-1, with estrogen into a conjugate may represent a novel, safe and potent, strategy to treat diabesity. Here we demonstrate that the central administration of GLP-1-estrogen conjugate reduced food reward, food intake, and body weight in rats. In order to determine the brain location of the interaction of GLP-1 with estrogen, we avail of single-photon emission computed tomography imaging of regional cerebral blood flow and pinpoint a brain site unexplored for its role in feeding and reward, the supramammillary nucleus (SUM) as a potential target of the conjugated GLP-1-estrogen. We confirm that conjugated GLP-1 and estrogen directly target the SUM with site-specific microinjections. Additional microinjections of GLP-1-estrogen into classic energy balance controlling nuclei, the lateral hypothalamus (LH) and the nucleus of the solitary tract (NTS) revealed that the metabolic benefits resulting from GLP-1-estrogen injections are mediated through the LH and to some extent by the NTS. In contrast, no additional benefit of the conjugate was noted on food reward when the compound was microinjected into the LH or the NTS, identifying the SUM as the only neural substrate identified here to underlie the reward reducing benefits of GLP-1 and estrogen conjugate. Collectively we discover a surprising neural substrate underlying food intake and reward effects of GLP-1 and estrogen and uncover a new brain area capable of regulating energy balance and reward.

Exposure to stress induces profound physiological and behavioral changes in the organisms and some of these changes may be important regarding stress-induced pathologies and animal models of psychiatric diseases. Consequences of stress are dependent on the duration of exposure to stressors (acute, chronic), but also of certain characteristics such as intensity, controllability, and predictability. If some biological variables were able to reflect these characteristics, they could be used to predict negative consequences of stress. Among the myriad of physiological changes caused by stress, only a restricted number of variables appears to reflect the intensity of the situation, mainly plasma levels of ACTH and adrenaline. Peripheral hypothalamic-pituitary-adrenal (HPA) hormones (ACTH and corticosterone) are also able to reflect fear conditioning. In contrast, the activation of the HPA axis is not consistently related to anxiety as evaluated by classical tests such as the elevated plus-maze. Similarly, there is no consistent evidence about the sensitivity of the HPA axis to psychological variables such as controllability and predictability, despite the fact that: (a) lack of control over aversive stimuli can induce behavioral alterations not seen in animals which exert control, and (b) animals showed clear preference for predictable versus unpredictable stressful situations. New studies are needed to re-evaluate the relationship between the HPA axis and psychological stress characteristics using ACTH instead of corticosterone and taking advantages of our current knowledge about the regulation of this important stress system.

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We sought to determine whether the orexigenic hormone, ghrelin, is involved in the intrinsic regulation of food choice in rats. Ghrelin would seem suited to serve such a role given that it signals hunger information from the stomach to brain areas important for feeding control, including the hypothalamus and reward system (e.g. ventral tegmental area, VTA). Thus, in rats offered a choice of palatable foods (sucrose pellets and lard) superimposed on regular chow for 2 weeks, we explored whether acute central delivery of ghrelin (intracerebroventricular (ICV) or intra-VTA) is able to redirect their dietary choice. The major unexpected finding is that, in rats with high baseline lard intake, acute ICV ghrelin injection increased their chow intake over 3-fold, relative to vehicle-injected controls, measured at both 3 hr and 6 hr after injection. Similar effects were observed when ghrelin was delivered to the VTA, thereby identifying the VTA as a likely contributing neurobiological substrate for these effects. We also explored food choice after an overnight fast, when endogenous ghrelin levels are elevated, and found similar effects of dietary choice to those described for ghrelin. These effects of fasting on food choice were suppressed in models of suppressed ghrelin signaling (i.e. peripheral injection of a ghrelin receptor antagonist to rats and ghrelin receptor (GHSR) knock-out mice), implicating a role for endogenous ghrelin in the changes in food choice that occur after an overnight fast. Thus, in line with its role as a gut-brain hunger hormone, ghrelin appears to be able to acutely alter food choice, with notable effects to promote “healthy” chow intake, and identify the VTA as a likely contributing neurobiological substrate for these effects.

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