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author:("fostera, kelp")
1.  Novel α-MSH analog causes weight loss in obese rats and minipigs and improves insulin sensitivity 
The Journal of Endocrinology  2014;220(2):97-107.
Obesity is a major burden to people and to health care systems around the world. The aim of the study was to characterize the effect of a novel selective α-MSH analog on obesity and insulin sensitivity. The subchronic effects of the selective MC4-R peptide agonist MC4-NN1-0182 were investigated in diet-induced obese (DIO) rats and DIO minipigs by assessing the effects on food intake, energy consumption, and body weight. The acute effect of MC4-NN1-0182 on insulin sensitivity was assessed by a euglycemic–hyperinsulinemic clamp study in normal rats. Three weeks of treatment of DIO rats with MC4-NN1-0182 caused a decrease in food intake and a significant decrease in body weight 7±1%, P<0.05 compared with 3±1% increase with the vehicle control. In DIO minipigs, 8 weeks of treatment with MC4-NN1-0182 resulted in a body weight loss of 13.3±2.5 kg (13±3%), whereas the vehicle control group had gained 3.7±1.4 kg (4±1%). Finally, clamp studies in normal rats showed that acute treatment with MC4-NN1-0182 caused a significant increase in glucose disposal (Rd) compared with vehicle control (Rd, mg/kg per min, 17.0±0.7 vs 13.9±0.6, P<0.01). We demonstrate that treatment of DIO rats or minipigs with a selective MC4-R peptide agonist causes weight loss. Moreover, we have demonstrated weight-independent effects on insulin sensitivity. Our observations identify MC4 agonism as a viable target for the treatment of obesity and insulin resistance.
doi:10.1530/JOE-13-0284
PMCID: PMC3888513  PMID: 24204009
obesity; insulin resistance; hyperinsulinemic–euglycemic clamp; melanocortin receptor 4; agonist; ISI
2.  Characterisation of Age-Dependent Beta Cell Dynamics in the Male db/db Mice 
PLoS ONE  2013;8(12):e82813.
Aim
To characterise changes in pancreatic beta cell mass during the development of diabetes in untreated male C57BLKS/J db/db mice.
Methods
Blood samples were collected from a total of 72 untreated male db/db mice aged 5, 6, 8, 10, 12, 14, 18, 24 and 34 weeks, for measurement of terminal blood glucose, HbA1c, plasma insulin, and C-peptide. Pancreata were removed for quantification of beta cell mass, islet numbers as well as proliferation and apoptosis by immunohistochemistry and stereology.
Results
Total pancreatic beta cell mass increased significantly from 2.1 ± 0.3 mg in mice aged 5 weeks to a peak value of 4.84 ± 0.26 mg (P < 0.05) in 12-week-old mice, then gradually decreased to 3.27 ± 0.44 mg in mice aged 34 weeks. Analysis of islets in the 5-, 10-, and 24-week age groups showed increased beta cell proliferation in the 10-week-old animals whereas a low proliferation is seen in older animals. The expansion in beta cell mass was driven by an increase in mean islet mass as the total number of islets was unchanged in the three groups.
Conclusions/Interpretation
The age-dependent beta cell dynamics in male db/db mice has been described from 5-34 weeks of age and at the same time alterations in insulin/glucose homeostasis were assessed. High beta cell proliferation and increased beta cell mass occur in young animals followed by a gradual decline characterised by a low beta cell proliferation in older animals. The expansion of beta cell mass was caused by an increase in mean islet mass and not islet number.
doi:10.1371/journal.pone.0082813
PMCID: PMC3855780  PMID: 24324833
3.  Drug-induced mild therapeutic hypothermia obtained by administration of a transient receptor potential vanilloid type 1 agonist 
Background
The use of mechanical/physical devices for applying mild therapeutic hypothermia is the only proven neuroprotective treatment for survivors of out of hospital cardiac arrest. However, this type of therapy is cumbersome and associated with several side-effects. We investigated the feasibility of using a transient receptor potential vanilloid type 1 (TRPV1) agonist for obtaining drug-induced sustainable mild hypothermia.
Methods
First, we screened a heterogeneous group of TRPV1 agonists and secondly we tested the hypothermic properties of a selected candidate by dose-response studies. Finally we tested the hypothermic properties in a large animal. The screening was in conscious rats, the dose-response experiments in conscious rats and in cynomologus monkeys, and the finally we tested the hypothermic properties in conscious young cattle (calves with a body weight as an adult human). The investigated TRPV1 agonists were administered by continuous intravenous infusion.
Results
Screening: Dihydrocapsaicin (DHC), a component of chili pepper, displayed a desirable hypothermic profile with regards to the duration, depth and control in conscious rats. Dose-response experiments: In both rats and cynomologus monkeys DHC caused a dose-dependent and immediate decrease in body temperature. Thus in rats, infusion of DHC at doses of 0.125, 0.25, 0.50, and 0.75 mg/kg/h caused a maximal ΔT (°C) as compared to vehicle control of -0.9, -1.5, -2.0, and -4.2 within approximately 1 hour until the 6 hour infusion was stopped. Finally, in calves the intravenous infusion of DHC was able to maintain mild hypothermia with ΔT > -3°C for more than 12 hours.
Conclusions
Our data support the hypothesis that infusion of dihydrocapsaicin is a candidate for testing as a primary or adjunct method of inducing and maintaining therapeutic hypothermia.
doi:10.1186/1471-2261-10-51
PMCID: PMC2966451  PMID: 20932337
4.  Increased susceptibility to cardiovascular effects of dihydrocapcaicin in resuscitated rats. Cardiovascular effects of dihydrocapsaicin 
Background
Survivors of a cardiac arrest often have persistent cardiovascular derangements following cardiopulmonary resuscitation including decreased cardiac output, arrhythmias and morphological myocardial damage. These cardiovascular derangements may lead to an increased susceptibility towards the external and internal environment of the cardiovascular system as compared to the healthy situation.
Methods
Here we tested the hypothesis that the cardiovascular system in healthy rats and rats resuscitated from a cardiac arrest may be differentially affected by a transient receptor potential vanilloid type 1 agonist, by continuous intravenous infusion of dihydrocapsaicin (DHC).
Results
Compared to baseline, infusion of DHC caused an initial increase in mean arterial blood pressure in both healthy and resuscitated rats of 25% and 10%, respectively. Also, we observed an initial response of tachycardia in both healthy and resuscitated rats of 30% and 20%, respectively. Then, at high levels of DHC infusion (> 2.0 mg/kg/hr) we observed two single episodes of transient bradycardia and hypotension in 33% of the healthy rats, which was consistent with a TRPV1 agonist induced Bezold-Jarisch reflex. In contrast, in resuscitated rats we observed multiple episodes of bradycardia/hypotension in 100% of the rats and at a dose of DHC of 0.65 mg/kg/hr. Notably, this DHC effect could be completely blocked in the resuscitated rats by pre-treatment with atropine, a muscarinic acetylcholine antagonist.
Conclusions
Our results indicate that the susceptibility of the rats towards TRPV1 agonist induced Bezold-Jarisch reflex is increased in those resuscitated from cardiac arrest compared to the healthy situation.
doi:10.1186/1471-2261-10-39
PMCID: PMC2939536  PMID: 20807439

Results 1-4 (4)