Stress and Energy Homeostasis
Maintaining energy homeostasis in the presence of diverse challenges, such as starvation, exercise or high fat diet, requires numerous adaptive responses in both central and peripheral tissues. Recent studies have clearly demonstrated that urocortin 2 and urocortin 3, acting through their specific type 2 CRF receptor (CRFR2), can serve as autocrine and/or paracrine regulators of glucose homeostasis by modulating insulin sensitivity in skeletal muscle or by regulating glucose-induced insulin secretion in the beta cells of the pancreas, respectively. The anatomical distribution of urocortin 2, urocortin 3 and CRFR2 within peripheral and central tissues key to regulation of energy homeostasis, together with the robust metabolic phenotypes of mice deficient for these factors leave them poised as major new players in this field. The long-term objective of our research is to examine the role of central and peripheral CRF receptor type 2 and its specific ligands, urocortin-2 and 3, in modulating energy homeostasis and metabolic functions in response to challenge.
Further insights into the detailed physiology of this system will be aided by the generation of specific transgenic animal models for manipulation of expression levels of the receptor or ligands. Study of such models will facilitate our understanding of the specific roles of central or peripheral CRFR2 in modulating metabolic functions. Likewise, understanding of the detailed regulation of central and peripheral CRFR2 and urocortins under different physiological conditions (basal or challenged) will also contribute to elucidating the cellular and molecular mechanisms mediating their effects. The novel functions for CRFR2 and its specific ligands urocortin 2 and urocrtin-3 as local regulators of glucose uptake in muscle and of insulin secretion in pancreas, will not only add to out current understanding of the physiology of energy metabolism, but are of potential interest as therapeutic targets for the management of type 2 diabetes and other metabolic disorders.
Schematic representation summarizing the proposed roles of central and peripheral CRF/urocortin peptides and receptors in modulating glucose homeostasis. Following stressful stimuli, glucocorticoid exposure resulting from HPA axis activation by hypothalamic CRF, and changes in autonomic activity will modulate skeletal muscle, pancreatic and hepatic functions. CRF and urocortins, acting via both type 1 and type 2 CRF receptors in the brain, will modulate food intake and glucose homeostasis. Peripherally, urocortin 2 produced in skeletal muscle and acting locally at CRF2 will regulate glucose uptake in skeletal muscle by inhibiting insulin signaling. Urocortin 3, produced by the pancreatic b-cells, regulates high glucose-induced insulin secretion. (Kuperman & Chen, TEM 2008).
Summary of selected projects:
Perifornical Urocortin-3 mediates the link between stress-induced anxiety and energy homeostasis
In response to physiological or psychological challenges, the brain activates behavioral and neuroendocrine systems linked to both metabolic and emotional outputs designed to adapt to the demand. However, dysregulation of integration of these physiological responses to challenge can have severe psychological and physiological consequences, and inappropriate regulation, disproportional intensity, or chronic or irreversible activation of the stress response is linked to the etiology and pathophysiology of mood and metabolic disorders. Using a novel transgenic mouse model and lentiviral approach, we demonstrate the involvement of the hypothalamic Urocortin-3 neuropeptide, a specific ligand for the type 2 corticotropin-releasing factor receptor, in modulating septal and hypothalamic nuclei, responsible for anxiety-like behaviors and metabolic functions, respectively. These results position Urocortin-3 as a new neuromodulator linking stress-induced anxiety and energy homeostasis and pave the way towards better understanding of the mechanisms that mediate the reciprocal relationships between stress, mood and metabolic disorders. (Kuperman et al., Perifornical Urocortin-3 mediates the link between stress-induced anxiety and energy homeostasis. Proc Natl Acad Sci U S A 107:8393-8398, 2010).
Establishment of site-specific and inducible Urocortin-3 over-expressing transgenic mouse model. (A) Schematic representation of the tetracycline-responsive regulatory system for transcriptional transactivation in a combined transgenic mouse and lentiviral systems. (B and C) Injection of the transactivator (‘effector virus’) into a specific site of the transgenic mouse brain, will result in incorporation of the rtTA expressing sequence at the infected neuron, ensuring constant and stable expression. In the presence of the inducer doxycycline (Dox), the rtTA protein binds the TRE and activates transcription of Ucn3 at the injection site. The rtTA lentiviruses were injected to the rostral perifornical (rPFA), which endogenously expresses Ucn3 and projects to the LS and the VMH. In the presence of Dox, rPFA-Ucn3 is over-expressed and its release at the LS and VMH nuclei is intensified. (D-F) Immunostaining of lateral septal Ucn3 terminal fields. In-situ hybridization demonstrating lateral septal CRFR2 mRNA expression (D). Immunostaining for lateral septal Ucn3 terminal fields (fibers immunostaining) obtained from mouse that was not treated (E) or treated (F) with Dox. rtTA, reverse transactivator. TRE, tetracycline response element. LS, lateral septum. VMH, ventromedial hypothalamus. (For further information on this figure, please refer to the article by Kuperman et al., Proc Natl Acad Sci U S A 107:8393-8398, 2010).
