Publications (11)85.36 Total impact
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Article: Deficiency of the RIIβ subunit of PKA affects locomotor activity and energy homeostasis in distinct neuronal populations.
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ABSTRACT: Targeted disruption of RIIβ-protein kinase A (PKA) in mice leads to a lean phenotype, increased nocturnal locomotor activity, and activation of brown adipose tissue. Because RIIβ is abundantly expressed in both white and brown adipose tissue as well as the brain, the contribution of neuronal vs. peripheral PKA to these phenotypes was investigated. We used a Cre-Lox strategy to reexpress RIIβ in a tissue-specific manner in either adipocytes or neurons. Mice with adipocyte-specific RIIβ reexpression remained hyperactive and lean, but pan-neuronal RIIβ reexpression reversed both phenotypes. Selective RIIβ reexpression in all striatal medium spiny neurons with Darpp32-Cre corrected the hyperlocomotor phenotype, but the mice remained lean. Further analysis revealed that RIIβ reexpression in D2 dopamine receptor-expressing medium spiny neurons corrected the hyperlocomotor phenotype, which demonstrated that the lean phenotype in RIIβ-PKA-deficient mice does not develop because of increased locomotor activity. To identify the neurons responsible for the lean phenotype, we used specific Cre-driver mice to reexpress RIIβ in agouti-related peptide (AgRP)-, proopiomelanocortin (POMC)-, single-minded 1 (Sim1)-, or steroidogenic factor 1 (SF1)-expressing neurons in the hypothalamus, but observed no rescue of the lean phenotype. However, when RIIβ was reexpressed in multiple regions of the hypothalamus and striatum driven by Rip2-Cre, or specifically in GABAergic neurons driven by Vgat-ires-Cre, both the hyperactive and lean phenotypes were completely corrected. Bilateral injection of adeno-associated virus1 (AAV1)-Cre directly into the hypothalamus caused reexpression of RIIβ and partially reversed the lean phenotype. These data demonstrate that RIIβ-PKA deficiency in a subset of hypothalamic GABAergic neurons leads to the lean phenotype.Proceedings of the National Academy of Sciences 04/2013; · 9.68 Impact Factor -
Article: Mice lacking δ-opioid receptors resist the development of diet-induced obesity.
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ABSTRACT: Pharmacological manipulation of opioid receptors alters feeding behavior. However, the individual contributions of each opioid receptor subtype on energy balance remain largely unknown. Herein, we investigated whether genetic disruption of the δ-opioid receptor (DOR) also controls energy homeostasis. Mice lacking DOR and wild-type mice were fed with standard diet and high-energy diet (HED). Mice were analyzed in vivo with the indirect calorimetry system, and tissues were analyzed by real-time PCR and Western blot analysis. DOR-knockout (KO) mice gained less weight (P<0.01) and had lower fat mass (P<0.01) when compared to WT mice fed an HED. Although DOR-KO mice were hyperphagic, they showed higher energy expenditure (P<0.05), which was the result of an increased activation of the thermogenic program in brown adipose tissue. The increased nonshivering thermogenesis involved the stimulation of uncoupling protein 1 (UCP1; P<0.01), peroxisome proliferator-activated receptor γ coactivator (PGC1α; P<0.05), and fibroblast growth factor 21 (FGF21; P<0.01). DOR deficiency also led to an attenuation of triglyceride content in the liver (P<0.05) in response to an HED. These findings reveal a novel role of DOR in the control of thermogenic markers and energy expenditure, and they provide a potential new therapeutic approach for the treatment of obesity.The FASEB Journal 05/2012; 26(8):3483-92. · 5.71 Impact Factor -
Article: CNS opioid signaling separates cannabinoid receptor 1-mediated effects on body weight and mood-related behavior in mice.
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ABSTRACT: Existing monotherapies for the treatment of obesity provide only modest weight loss and/or have adverse side effects, and this is also the case with the cannabinoid receptor 1 (CB1) inverse agonist, rimonabant. We aimed to investigate the possibility of improving efficacy and reducing side effects of rimonabant by cotreatment with opioid system antagonists. Using both genetic and pharmacological removal of opioid signaling in mice, we investigated changes in body weight, food intake, and fat mass as well as behavioral outcomes of interactions between opioid ligands and the CB1 using the inverse agonist, rimonabant. The ability of rimonabant to reduce weight is enhanced by removal of with μ-opioid receptor signaling, while not being greatly affected by κ-opioid receptor blockade. Additionally, lack of opioid signaling, especially κ-opioid receptor, attenuated the ability of rimonabant to decrease immobility time in the Porsolt forced-swim test, a preclinical model of depression. These results indicate that the endogenous opioid system is involved in modulating both the metabolic and mood effects of rimonabant.Endocrinology 08/2011; 152(10):3661-7. · 4.46 Impact Factor -
Article: A model of binge-like eating behavior in mice that does not require food deprivation or stress.
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ABSTRACT: Binge eating disorder (BED) is characterized by excessive food intake during a short period of time and is often associated with obesity. Mouse models of binge-like eating behavior are lacking making it difficult to employ genetic models in the identification of mechanisms regulating excessive eating. We report a rapid and simple model to induce binge-like eating behavior in mice that does not require food deprivation or exogenous stressors. Weekly 24 h access to a nutritionally complete high energy diet (HED), along with continuous access to standard chow, resulted in a significant increase in HED intake following its presentation compared to mice that had continuous access to both diets. Mice exhibiting binge-like eating consumed one-third of their normal total daily caloric intake within 2.5 h of HED presentation. Moreover, total 24-h caloric intakes were increased by 50% in mice exhibiting binge-like eating. Following repeated cycles, binge-like eating of the HED was maintained over several weeks with no evidence of habituation or significant alterations in body weight and adiposity. Pharmacological evaluation of binge-like eating behavior was performed using clinically employed compounds. Interestingly, binge-like eating was dose-dependently decreased by fluoxetine, but not baclofen or topiramate. These data support clinical validation of this mouse model of binge-like eating behavior, as fluoxetine has been shown to reduce binge frequency in human subjects with BED. The availability of transgenic and knockout mice will allow for the determination of genes that are involved in the initiation and maintenance of binge-like eating behavior.Obesity 03/2010; 18(9):1710-7. · 4.28 Impact Factor -
Article: kappa-Opioid receptors control the metabolic response to a high-energy diet in mice.
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ABSTRACT: General opioid receptor antagonists reduce food intake and body weight in rodents, but the contributions of specific receptor subtypes are unknown. We examined whether genetic deletion of the kappa-opioid receptor (KOR) in mice alters metabolic physiology. KOR-knockout (KO) and wild-type (WT) mice were fed a high-energy diet (HED) for 16 wk. KO mice had 28% lower body weight and 45% lower fat mass when compared to WT mice fed an HED. No differences in caloric intake were found. An HED reduced energy expenditure in WT mice, but not in KO mice. KOR deficiency led to an attenuation of triglyceride synthesis in the liver. Malonyl CoA levels were also reduced in response to an HED, thereby promoting hepatic beta-oxidation. Glycemic control was also found to be improved in KO mice. These data suggest a key role for KORs in the central nervous system regulation of the metabolic adaptation to an HED, as we were unable to detect expression of KOR in liver, white adipose tissue, or skeletal muscle in WT mice. This study provides the first evidence that KORs play an essential physiological role in the control of hepatic lipid metabolism, and KOR activation is a permissive signal toward fat storage.-Czyzyk, T. A., Nogueiras, R., Lockwood, J. F., McKinzie, J. H., Coskun, T., Pintar, J. E., Hammond, C., Tschöp, M. H., Statnick, M. A. kappa-Opioid receptors control the metabolic response to a high-energy diet in mice.The FASEB Journal 11/2009; 24(4):1151-9. · 5.71 Impact Factor -
Article: GOAT links dietary lipids with the endocrine control of energy balance.
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ABSTRACT: Central nervous system nutrient sensing and afferent endocrine signaling have been established as parallel systems communicating metabolic status and energy availability in vertebrates. The only afferent endocrine signal known to require modification with a fatty acid side chain is the orexigenic hormone ghrelin. We find that the ghrelin O-acyl transferase (GOAT), which is essential for ghrelin acylation, is regulated by nutrient availability, depends on specific dietary lipids as acylation substrates and links ingested lipids to energy expenditure and body fat mass. These data implicate the ghrelin-GOAT system as a signaling pathway that alerts the central nervous system to the presence of dietary calories, rather than to their absence as is commonly accepted.Nature medicine 07/2009; 15(7):741-5. · 27.14 Impact Factor -
Article: Disruption of the RIIbeta subunit of PKA reverses the obesity syndrome of Agouti lethal yellow mice.
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ABSTRACT: Agouti lethal yellow (A(y)) mice express agouti ectopically because of a genetic rearrangement at the agouti locus. The agouti peptide is a potent antagonist of the melanocortin 4 receptor (MC4R) expressed in neurons, and this leads to hyperphagia, hypoactivity, and increased fat mass. The MC4R signals through Gs and is thought to stimulate the production of cAMP and activation of downstream cAMP effector molecules such as PKA. Disruption of the RIIbeta regulatory subunit gene of PKA results in release of the active catalytic subunit and an increase in basal PKA activity in cells where RIIbeta is highly expressed. Because RIIbeta is expressed in neurons including those in the hypothalamic nuclei where MC4R is prominent we tested the possibility that the RIIbeta knockout might rescue the body weight phenotypes of the A(y) mice. Disruption of the RIIbeta PKA regulatory subunit gene in mice leads to a 50% reduction in white adipose tissue and resistance to diet-induced obesity and hyperglycemia. The RIIbeta mutation rescued the elevated body weight, hyperphagia, and obesity of A(y) mice. Partial rescue of the A(y) phenotypes was even observed on an RIIbeta heterozygote background. These results suggest that the RIIbeta gene mutation alters adiposity and locomotor activity by modifying PKA signaling pathways downstream of the agouti antagonism of MC4R in the hypothalamus.Proceedings of the National Academy of Sciences 02/2008; 105(1):276-81. · 9.68 Impact Factor -
Article: Deletion of peptide amidation enzymatic activity leads to edema and embryonic lethality in the mouse.
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ABSTRACT: Peptidylglycine alpha-amidating monooxygenase (PAM) catalyzes the COOH-terminal amidation of peptide hormones. We previously had found high expression of PAM in several regions of the developing rodent. To determine the function of PAM during mouse embryogenesis, we produced a null mutant of the PAM gene. Homozygous mutants die in utero between e14.5 and e15.5 with severe edema that is likely due to cardiovascular deficits. These defects include thinning of the aorta and carotid arteries and are very similar to those of the recently characterized adrenomedullin (AM) gene KO despite the presence of elevated immunoreactive AM in PAM KO embryos. No peptide amidation activity was detected in PAM mutant embryos, and there was no moderation of the AM-like phenotype that could be expected if any alternative peptide amidation mechanism exists in the mouse. Despite the proposed contribution of amidated peptides to neuronal cell proliferation, no alteration in neuroblast proliferation was observed in homozygous mutant embryos prior to lethality. Mice heterozygous for the mutant PAM allele develop normally and express wildtype levels of several amidated peptides despite having one half the wildtype levels of PAM activity and PAM protein. Nonetheless, both an increase in adiposity and a mild glucose intolerance developed in aged (>10 months) heterozygous mice compared to littermate controls. Ablation of PAM thus demonstrates an essential function for this gene during mouse development, while alterations in PAM activity in the adult may underlie more subtle physiologic effects.Developmental Biology 12/2005; 287(2):301-13. · 4.07 Impact Factor -
Article: Neuropathic pain activates the endogenous kappa opioid system in mouse spinal cord and induces opioid receptor tolerance.
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ABSTRACT: Release of endogenous dynorphin opioids within the spinal cord after partial sciatic nerve ligation (pSNL) is known to contribute to the neuropathic pain processes. Using a phosphoselective antibody [kappa opioid receptor (KOR-P)] able to detect the serine 369 phosphorylated form of the KOR, we determined possible sites of dynorphin action within the spinal cord after pSNL. KOR-P immunoreactivity (IR) was markedly increased in the L4-L5 spinal dorsal horn of wild-type C57BL/6 mice (7-21 d) after lesion, but not in mice pretreated with the KOR antagonist nor-binaltorphimine (norBNI). In addition, knock-out mice lacking prodynorphin, KOR, or G-protein receptor kinase 3 (GRK3) did not show significant increases in KOR-P IR after pSNL. KOR-P IR was colocalized in both GABAergic neurons and GFAP-positive astrocytes in both ipsilateral and contralateral spinal dorsal horn. Consistent with sustained opioid release, KOR knock-out mice developed significantly increased tactile allodynia and thermal hyperalgesia in both the early (first week) and late (third week) interval after lesion. Similarly, mice pretreated with norBNI showed enhanced hyperalgesia and allodynia during the 3 weeks after pSNL. Because sustained activation of opioid receptors might induce tolerance, we measured the antinociceptive effect of the kappa agonist U50,488 using radiant heat applied to the ipsilateral hindpaw, and we found that agonist potency was significantly decreased 7 d after pSNL. In contrast, neither prodynorphin nor GRK3 knock-out mice showed U50,488 tolerance after pSNL. These findings suggest that pSNL induced a sustained release of endogenous prodynorphin-derived opioid peptides that activated an anti-nociceptive KOR system in mouse spinal cord. Thus, endogenous dynorphin had both pronociceptive and antinociceptive actions after nerve injury and induced GRK3-mediated opioid tolerance.Journal of Neuroscience 06/2004; 24(19):4576-84. · 7.11 Impact Factor -
Article: Prolonged kappa opioid receptor phosphorylation mediated by G-protein receptor kinase underlies sustained analgesic tolerance.
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ABSTRACT: Kappa opioid receptor (KOR) desensitization was previously shown to follow agonist-dependent phosphorylation of serine 369 by G-protein receptor kinase (GRK) and beta-arrestin binding in transfected cells. To study the in vivo effects induced by phosphorylation of KOR(S369), C57Bl/6 mice were administered single or repeated doses of the KOR agonist, U50,488, and isolated brain glycoprotein was probed with an antibody, KOR-P, that specifically recognized phosphoserine 369 KOR. Western blot analysis using KOR-P antibody showed that labeling intensity increased after either single or repeated treatment of mice with U50,488 by 59 +/- 22% and 101 +/- 29%, respectively. In contrast, there was no change in labeling intensity by nonphosphoselective KOR antibodies following acute or chronic in vivo treatment with kappa agonist. Moreover, mice lacking GRK3 showed no increase in KOR-P labeling and developed significantly less analgesic tolerance following treatment with kappa agonist. The result suggests that tolerance to kappa agonists includes phosphorylation of serine 369 within KOR by GRK3. Recovery of analgesic potency and reduction of elevated KOR-P labeling in wild-type mice both required 2 weeks to return to base line. Consistent with these results, in vitro phosphorylation by GRK3 of KOR isolated from tolerant mice resulted in 46 +/- 7% less (32)P incorporation than in KOR isolated from untreated mice. In addition, in vitro (32)P incorporation returned to base line levels only in KOR isolated from tolerant mice allowed to recover for 2 weeks. The coincident reversal of analgesic tolerance and slow return to a basal phosphorylation state matched the regeneration rate of functional kappa receptors following irreversible antagonism and suggested that receptor replacement rather than dephosphorylation was required to restore sensitivity.Journal of Biological Chemistry 02/2004; 279(3):1810-8. · 4.77 Impact Factor -
Article: Targeted mutagenesis of processing enzymes and regulators: implications for development and physiology.
Journal of Neuroscience Research 12/2003; 74(3):446-55. · 2.74 Impact Factor
Top co-authors
Top Journals
Institutions
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2009–2010
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Eli Lilly
- Lilly Research Laboratories
Indianapolis, IN, USA
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2008
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University of Washington Seattle
- Department of Pharmacology
Seattle, WA, USA
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2003–2005
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Robert Wood Johnson University Hospital
New Brunswick, NJ, USA
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