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ABSTRACT: Obesity is caused by an imbalance between energy intake and expenditure and has become a major health-care problem in western society. The central melanocortin system plays a crucial role in the regulation of feeding and energy expenditure, and functional loss of melanocortin receptor 4 (MC4R) is the most common genetic cause of human obesity. In this study, we present the first functional Mc4r knockout model in the rat, resulting from an N-ethyl-N-nitrosourea mutagenesis-induced point mutation. In vitro observations revealed impaired membrane-binding and subsequent nonfunctionality of the receptor, whereas in vivo observations showed that functional loss of MC4R increased body weight, food intake, white adipose mass, and changed substrate preference. In addition, intracerebroventricular (ICV) administration of Agouti-Related Protein(79-129) (AgRP(79-129)), an MC4R inverse agonist, or Melanotan-II (MTII), an MC4R agonist, did affect feeding behavior in wild-type rats but not in homozygous mutant rats, confirming complete loss of MC4R function in vivo. Finally, ICV administration of MTII induced excessive grooming behavior in wild-type rats, whereas this effect was absent in homozygous mutant rats, indicating that MTII-induced grooming behavior is exclusively regulated via MC4R pathways. Taken together, we expect that the MC4R rat model described here will be a valuable tool for studying monogenic obesity in humans. More specifically, the relative big size and increased cognitive capacity of rats as compared to mice will facilitate complex behavioral studies and detailed mechanistic studies regarding central function of MC4R, both of which ultimately may help to further understand the specific mechanisms that induce obesity during loss of MC4R function.
Obesity 04/2011; 20(3):612-21. · 4.28 Impact Factor
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ABSTRACT: Obesity is caused by an imbalance between energy intake and expenditure and has become a major health-care problem in western society. The central melanocortin system plays a crucial role in the regulation of feeding and energy expenditure, and functional loss of melanocortin receptor 4 (MC4R) is the most common genetic cause of human obesity. In this study, we present the first functional Mc4r knockout model in the rat, resulting from an N-ethyl-N-nitrosourea mutagenesis–induced point mutation. In vitro observations revealed impaired membrane-binding and subsequent nonfunctionality of the receptor, whereas in vivo observations showed that functional loss of MC4R increased body weight, food intake, white adipose mass, and changed substrate preference. In addition, intracerebroventricular (ICV) administration of Agouti-Related Protein79–129 (AgRP79–129), an MC4R inverse agonist, or Melanotan-II (MTII), an MC4R agonist, did affect feeding behavior in wild-type rats but not in homozygous mutant rats, confirming complete loss of MC4R function in vivo. Finally, ICV administration of MTII induced excessive grooming behavior in wild-type rats, whereas this effect was absent in homozygous mutant rats, indicating that MTII-induced grooming behavior is exclusively regulated via MC4R pathways. Taken together, we expect that the MC4R rat model described here will be a valuable tool for studying monogenic obesity in humans. More specifically, the relative big size and increased cognitive capacity of rats as compared to mice will facilitate complex behavioral studies and detailed mechanistic studies regarding central function of MC4R, both of which ultimately may help to further understand the specific mechanisms that induce obesity during loss of MC4R function.
Obesity 04/2011; 20(3):612-621. · 4.28 Impact Factor
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ABSTRACT: In animal models, devices such as indwelling catheters and intracranial cannulae are often fixed on the skull to allow sampling or injection in the freely moving animal. The most commonly used method to fixate these devices is by embedding them in a 'helmet' of cement which is fixed to the skull with screws. Methylmethacrylate cement is commonly used for this purpose. The disadvantages of this cement are the high polymerization temperature, poor bonding to the bone and long hardening time. We have evaluated the use of glass ionomer cement, carboxylat cement and cyanoacrylic glue as alternative for methylmethacrylate cement. Temperature increase during polymerization of methylmethacrylate cement and glass ionomer cement was measured in the cement on the skull and in the brain of 14 rats in an acute model. In a chronic model, 52 rats and 91 mice were equipped with a 'helmet' of one of the cements. The glass ionomer 'helmets' were applied without or with pretreatment of the skull. The attachment of the cement to the skull was checked every day. After four weeks the bonding strengths of the cements were measured. The glass ionomer cement had less temperature increase during polymerization and good bonding capabilities when compared with methylmethacrylate cement. Mechanical pretreatment of the skull resulted in a significant increase in bonding strength of glass ionomer cement in mice and rats as compared with chemical pretreatment. Furthermore, glass ionomer cement had a shorter hardening time than methylmethacrylate cement, and when the glass ionomer cement was used in prepacked capsules, it was possible to apply the cement sterilely and easily. Cyanoacrylic glue had good bonding capabilities to the skull of mice and is also a good substitute for methylmethacrylate cement.
Laboratory Animals 07/2010; 44(3):264-70. · 1.21 Impact Factor
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ABSTRACT: Activity-based anorexia (ABA) is considered an animal model of anorexia nervosa. In ABA, scheduled feeding in combination with voluntary wheel running leads to hyperactivity, reduced food intake, severe body weight loss and hypothermia. In this study it was investigated whether hyperactivity in ABA could be reduced by introducing a warm plate (which was voluntary accessible and did not influence ambient temperature) into a part of the cage. In ad libitum fed rats, the presence of the warm plate did not influence body temperature, running wheel activity (RWA), body weight or food intake. During ABA, however, rats preferred the warm plate and hypothermia was prevented, while hyperactivity and body weight loss were significantly reduced when compared to ABA rats without a plate. Correlation analysis revealed a significant association between basal body temperature and RWA during the light phase in ABA rats. However, there was no evidence that initiation of light phase RWA was a result of hypothermia. These data suggest that ABA rats prefer to prevent hypothermia passively by choosing a warm plate rather than actively regulating body temperature by hyperactivity.
Physiology & Behavior 07/2005; 85(2):151-7. · 2.87 Impact Factor
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ABSTRACT: Peripheral nerve regeneration has been studied extensively in the sciatic nerve crush model, at the level of both function and gene expression. The crush injury allows full recovery of sensory and motor function in about 3 weeks as assessed by the foot reflex withdrawal test and De Medinacelli walking patterns. We used the recently developed CatWalk paradigm to study walking patterns in more detail in mice and rats. We found that, following the recovery of sensory function, the animals developed a state of mechanical allodynia, which retreated slowly over time. The motor function, although fully recovered with the conventional methods, was revealed to be still impaired because the animals did not put weight on their previously injured paw. The development of neuropathic pain following successful sensory recovery has not been described before in crush-lesioned animals and may provide an important new parameter to assess full sensory recovery.
Brain Research 12/2004; 1027(1-2):67-72. · 2.73 Impact Factor
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ABSTRACT: The neurotrophic and neuroprotective potential of the alpha-melanocyte-stimulating hormone (alpha-MSH) analog cyclo-[Ac-Nle(4),Asp(5),D-Phe(7),Lys(10)]alpha-MSH-(4-10) amide (melanotan-II), a potent melanocortin receptor agonist, was investigated. The sciatic nerve crush model was used as a paradigm to investigate the neurotrophic properties of melanotan-II. Melanotan-II significantly enhanced the recovery of sensory function following a crush lesion of the sciatic nerve in the rat at a dose of 20 microg kg(-1) per 48 h, s.c., but not at a dose of 2 or 50 microg kg(-1). In addition, we observed that melanotan-II also possesses neuroprotective properties, as it partially protected the nerve from a toxic neuropathy induced by cisplatin. Thus, the present data for the first time demonstrate the effectiveness of the potent alpha-MSH analog melanotan-II in nerve regeneration and neuroprotection.
European Journal of Pharmacology 03/2003; 462(1-3):179-83. · 2.52 Impact Factor
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ABSTRACT: Homeobox genes encode transcription factors that play key roles in embryonic development of the nervous system. Dorsal root ganglia are part of the peripheral nervous system that arises from the neural crest. Several homeobox genes are known to play important roles in the development of neural crest and dorsal root ganglia. Some of these remain expressed in the adult dorsal root ganglia (DRG). In order to get more insight into the homeobox gene repertoire in adult rat DRG, we performed RT-PCR with degenerate primers and identified twenty-two homeobox genes. We found homeobox genes that were reported before in embryonic or adult DRG, as well as homeobox genes associated before with neural crest (derivatives). Some of the genes were not reported in relation to neural crest or DRG before. Two homeobox genes displayed sequence differences with their mouse counterparts, possibly being close homologues. The diversity of homeobox genes expressed in adult DRG suggests that gene regulatory events initiated during development remain operative in the mature DRG.
Neuroscience Research Communications 12/2002; 32(1):49 - 59.
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ABSTRACT: The efficacy of melanocortins (α-MSH and an ACTH-(4–9) analog, Org. 2766) in accelerating functional recovery from sciatic nerve damage following various types of subcutaneous and oral administration was assessed in the rat. Furthermore, the effectiveness of the local delivery of melanocortins to the site of injury was examined. An accelerated recovery was evident following subcutaneous constant delivery of Org.2766 from an osmotic mini-pump and from biodegradable polymere microspheres, and was as effective as repeated subcutaneous injections of α-MSH or Org.2766. Oral administration of Org.2766 was ineffective. Local application of Org.2766, achieved by wrapping a peptide-impregnated biodegradable gelatine foam matrix around the site of injury, facilitated recovery as well. The biodegradable microspheres and gelatine foam matrix may be of importance in eventual clinical use as effective vehicles for administration of melanocortins in the treatment of peripheral nerve damage.
European Journal of Pharmacology.
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ABSTRACT: Antagonists for the melanocortin receptor family were identified by analysis of the effects of four melanocortin analogues on α-MSH(α-melanocyte-stimulating hormone)-induced cAMP accumulation in 293 human embryonal kidney (HEK) cells that expressed either the rat melanocortin MC3 receptor, the human melanocortin MC4 receptor or the ovine melanocortin MC5 receptor. Two peptides, [D-Arg8]ACTH(adrenocorticotrope hormone)-(4–10) and [Pro8,10, Gly9]ACTH-(4–10), antagonized the action of α-MSH on the melanocortin MC4 and MC5 receptors, but not the melanocortin MC3 receptor. [Ala6]ACTH-(4–10) inhibited the α-MSH activation of the melanocortin MC3 and MC5, but only weakly antagonized the activation of the melanocortin MC4 receptor. [Phe-I7]ACTH-(4–10) antagonized the melanocortin MC3, MC4 and MC5 receptors equally well. These antagonists were also tested to block a behavioral response induced by α-MSH. α-MSH-induced excessive grooming behavior in rats was inhibited by [Phe-I7]ACTH-(4–10), [D-Arg8]ACTH-(4–10) and [Pro8,10,Gly9]ACTH-(4–10), but not by [Ala6]ACTH-(4–10). This suggests that α-MSH-induced excessive grooming behavior is mediated by melanocortin MC4 receptors.
European Journal of Pharmacology: Molecular Pharmacology.
