The Peptidic GHS-R antagonist [D-Lys3]GHRP-6 markedly improves adiposity and related metabolic abnormalities in a mouse model of postmenopausal obesity

Maletı́nská, Lenka; Matyšková, Resha; Maixnerová, Jana; Sýkora, David; Pýchová, Miroslava; Špolcová, Andrea; Blechová, Miroslava; Drápalová, J.; Lacinová, Z; Haluzı́k, Martin; Železná, Blanka

doi:10.1016/j.mce.2011.06.006

Cited by 39 publications

(23 citation statements)

References 37 publications

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“…Clegg et al (130) reported that ovariectomy did not increase food intake or body weight in transgenic mice with null mutations of the ghrelin receptor, suggesting a necessary role for estrogens. Maletínská et al (453), however, failed to detect any influence of estradiol treatment on the eating-inhibitory and weight-reducing effects of twice daily subcutaneous injections of the ghrelin antagonist [D-Lys3]GHRP-6 in ovariectomized mice fed chow or high-fat diet. A parsimonious potential resolution of these data is that estrogens act during early development to reduce the eating-stimulatory effect of ghrelin in adult mice.…”

Section: R1233 Sex Differences In the Physiology Of Eatingmentioning

confidence: 98%

Sex differences in the physiology of eating

Asarian

Geary²

2013

American Journal of Physiology-Regulatory, Integrative and Comp

414

349

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(HPG) axis function fundamentally affects the physiology of eating. We review sex differences in the physiological and pathophysiological controls of amounts eaten in rats, mice, monkeys, and humans. These controls result from interactions among genetic effects, organizational effects of reproductive hormones (i.e., permanent early developmental effects), and activational effects of these hormones (i.e., effects dependent on hormone levels). Male-female sex differences in the physiology of eating involve both organizational and activational effects of androgens and estrogens. An activational effect of estrogens decreases eating 1) during the periovulatory period of the ovarian cycle in rats, mice, monkeys, and women and 2) tonically between puberty and reproductive senescence or ovariectomy in rats and monkeys, sometimes in mice, and possibly in women. Estrogens acting on estrogen receptor-␣ (ER␣) in the caudal medial nucleus of the solitary tract appear to mediate these effects in rats. Androgens, prolactin, and other reproductive hormones also affect eating in rats. Sex differences in eating are mediated by alterations in orosensory capacity and hedonics, gastric mechanoreception, ghrelin, CCK, glucagon-like peptide-1 (GLP-1), glucagon, insulin, amylin, apolipoprotein A-IV, fatty-acid oxidation, and leptin. The control of eating by central neurochemical signaling via serotonin, MSH, neuropeptide Y, Agouti-related peptide (AgRP), melanin-concentrating hormone, and dopamine is modulated by HPG function. Finally, sex differences in the physiology of eating may contribute to human obesity, anorexia nervosa, and binge eating. The variety and physiological importance of what has been learned so far warrant intensifying basic, translational, and clinical research on sex differences in eating.neuroendocrinology; estrogens; testosterone; eating disorders; obesity SEX DIFFERENCES ARE PERVASIVE in physiology and medicine (51,64,73,109,110,466,797,826). The controls of eating and energy homeostasis are no exceptions. It was observed approximately 100 years ago that removal of the ovaries leads to marked accretion of adipose tissue in rats (697), that daily food intake expressed as kilocalories per gram body weight differs between male and female rats (778), and that food intake varies regularly through the ovarian cycle in intact female rats (674, 779). Sex differences in eating have been the subject of physiological research ever since. The clinical relevance of this work is increasingly evident. In the United States, women are approximately threefold more vulnerable than men to psychiatric eating disorders (346,351) and approximately twofold more vulnerable to severe and morbid obesity (BMI Ն 35 and 40 kg/m 2 , respectively, mass/height 2 ) (226). Women also appear to suffer more from these disorders in terms of physical and psychological functioning and quality of life (24,84,273,292,465,531,762). The increased obesity burden suffered by women is reflected in the fact that Ͼ80% of bariatric surgery patients in the U...

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Section: R1233 Sex Differences In the Physiology Of Eatingmentioning

confidence: 98%

Sex differences in the physiology of eating

Asarian

Geary²

2013

American Journal of Physiology-Regulatory, Integrative and Comp

414

349

View full text Add to dashboard Cite

show abstract

“…Trophic and protective effects on β-cells in humans and rodents (16,21,55) Inhibition of ghrelin in humans and rodents (17,19) Restoration of EPC/CAC number and function in DM patients and rodents (40) Muscle regeneration in rodents (27,39) Des-acyl ghrelin (glucose) in humans and rodents (34,54) Figure 1 Overview of des-acyl ghrelin actions, along with some references for further reading.…”

Section: The First Indicationsmentioning

confidence: 99%

“…DAG administration improves glucose metabolism and inhibits lipolysis in healthy volunteers (34) In obesity and obesity-associated type 2 diabetes, ghrelin levels are increased and DAG levels decreased Another report on the potential beneficial effects of antagonizing AG showed that the ghrelin receptor antagonist [D-Lys3]-GHRP-6, after 7 days of subcutaneous treatment, markedly decreased food intake in ovariectomized mice fed both high-fat and standard diets. Furthermore, Maletinska et al (34) reported that this AG antagonist reduced body weight, blood glucose, insulin, and leptin.…”

Section: Inhoff Et Al (17) and Neary Et Al (18))mentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Ghrelin: the differences between acyl- and des-acyl ghrelin

Delhanty

Neggers

Lely

2012

European Journal of Endocrinology

212

180

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Des-acyl ghrelin (DAG) is one of the three preproghrelin gene-encoded peptides. Compared with ghrelin and obestatin, it has not received the attention it deserves. DAG has long been considered an inert degradation product of acyl ghrelin (AG). Recent evidence, however, indicates that DAG behaves like a separate hormone. DAG can act together with AG, can antagonize AG, and seems to have AG-independent effects. Therefore, it is believed that DAG must activate its own receptor and that it may also interact with AG at this receptor. Of potential clinical importance is that an increasing number of studies suggest that DAG might be a functional inhibitor of ghrelin and that DAG can suppress ghrelin levels in humans. Therefore, DAG or DAG analogs might be good candidates for future treatment of metabolic disorders or other conditions in which antagonism of AG actions could be beneficial, such as diabetes, obesity, and Prader-Willi syndrome.

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“…insulin, and leptin levels and increased b-hydroxybutyrate levels and Ucp1 mRNA in brown adipose tissue. They concluded that the antagonism of ghrelin can be beneficial in obese individuals (26). Landgren et al (27,28) showed that GHS-R1a antagonism reduces the intake and selfadministration of sucrose in rats as well as saccharin intake in mice.…”

Section: European Journal Of Endocrinologymentioning

confidence: 99%

Does des-acyl ghrelin improve glycemic control in obese diabetic subjects by decreasing acylated ghrelin levels?

Özcan¹,

Neggers²,

Miller³

et al. 2014

European Journal of Endocrinology

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Objective: The objective of this study was to assess the effects of a continuous overnight infusion of des-acyl ghrelin (DAG) on acylated ghrelin (AG) levels and glucose and insulin responses to a standard breakfast meal (SBM) in eight overweight patients with type 2 diabetes. Furthermore, in the same patients and two additional subjects, the effects of DAG infusion on AG concentrations and insulin sensitivity during a hyperinsulinemic-euglycemic clamp (HEC) were assessed. Research design and methods: A double-blind, placebo-controlled cross-over study design was implemented, using overnight continuous infusions of 3 and 10 mg DAG/kg per h and placebo to study the effects on a SBM. During a HEC, we studied the insulin sensitivity. Results: We observed that, compared with placebo, overnight DAG administration significantly decreased postprandial glucose levels, both during continuous glucose monitoring and at peak serum glucose levels. The degree of improvement in glycemia was correlated with baseline plasma AG concentrations. Concurrently, DAG infusion significantly decreased fasting and postprandial AG levels. During the HEC, 2.5 h of DAG infusion markedly decreased AG levels, and the M-index, a measure of insulin sensitivity, was significantly improved in the six subjects in whom we were able to attain steady-state euglycemia. DAG administration was not accompanied by many side effects when compared with placebo. Conclusions: DAG administration improves glycemic control in obese subjects with type 2 diabetes through the suppression of AG levels. DAG is a good candidate for the development of compounds in the treatment of metabolic disorders or other conditions with a disturbed AG:DAG ratio, such as type 2 diabetes mellitus or Prader-Willi syndrome.

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The Peptidic GHS-R antagonist [D-Lys3]GHRP-6 markedly improves adiposity and related metabolic abnormalities in a mouse model of postmenopausal obesity

Cited by 39 publications

References 37 publications

Sex differences in the physiology of eating

Sex differences in the physiology of eating

MECHANISMS IN ENDOCRINOLOGY: Ghrelin: the differences between acyl- and des-acyl ghrelin

Does des-acyl ghrelin improve glycemic control in obese diabetic subjects by decreasing acylated ghrelin levels?

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