Improved insulin sensitivity and metabolic flexibility in ghrelin receptor knockout mice

Longo, Kenneth A.; Charoenthongtrakul, Soratree; Giuliana, Derek J.; Govek, Elizabeth; McDonagh, Thomas; Qi, Yong; DiStefano, Peter S.; Geddes, Brad J.

doi:10.1016/j.regpep.2008.03.011

Cited by 87 publications

(90 citation statements)

References 23 publications

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“…This has not been widely reported in the literature, and it is intriguing that different conclusions were found recently in ghrelin receptor knockout mice; they appeared to have increased RQ variability compared to controls. 33 Therefore, in our study ghrelin may have restored a 'lean' temporal pattern of substrate utilization in both obese and gastrectomy subjects simply by promoting greater RQ variability with meals.…”

mentioning

confidence: 64%

Ghrelin restores ‘lean-type’ hunger and energy expenditure profiles in morbidly obese subjects but has no effect on postgastrectomy subjects

et al. 2009

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Objective: To examine the effects of ghrelin on appetite and energy expenditure in lean, obese and postgastrectomy subjects. Design: A randomized, double-blind, placebo-controlled study. Patients: Nine lean subjects (mean body mass index (BMI) 23.5±3 kg/m 2 ) and nine morbidly obese subjects (mean BMI 51.4 ± 10 kg/m 2 ) and eight postgastrectomy subjects (mean BMI 22.4 ± 1.0 kg/m 2 ). Interventions: Subjects were infused with either intravenous ghrelin (5 pmol kg À1 min À1 ) or saline over 270 min. They were given a fixed energy breakfast followed by a free buffet lunch towards the end of the infusion. Main outcome measures: Visual analogue scales were used to record hunger and energy expenditure was measured by indirect calorimetry. Results: Ghrelin increased energy intake at the buffet lunch in lean subjects (a 41% increase, Po0.01) and obese subjects (35% increase, P ¼ 0.04) but not in postgastrectomy subjects. Lean subjects showed a characteristic preprandial rise and postprandial fall in hunger scores, which was exaggerated by ghrelin infusion. Obese subjects showed little variation in hunger scores, but a 'lean-type' pattern was restored when given exogenous ghrelin. Ghrelin had no effect on resting metabolic rate but did increase respiratory quotient (RQ) in obese subjects. Ghrelin also increased RQ variability over time in all three groups (ANOVA, Po0.001). Conclusions: Hunger scores are abnormal in the obese, perhaps because of impaired ghrelin secretion. The effect of ghrelin in restoring normal hunger profiles in the obese suggests causality, confirming an important role in eating behaviour. Ghrelin also increases RQ in obese humans and increased RQ variability in all groups. This suggests that ghrelin regulates substrate utilization and may promote metabolic flexibility.

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confidence: 64%

Ghrelin restores ‘lean-type’ hunger and energy expenditure profiles in morbidly obese subjects but has no effect on postgastrectomy subjects

et al. 2009

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“…Obesity is characterized by a tendency for decreased levels of DAG but unchanged AG levels, indicating a state of relative DAG deficiency where DAG levels are regulated by body weight (8,9). Moreover, insulin-resistant obese subjects have an elevated AG:DAG ratio when compared with insulin-sensitive obese subjects (10,11,12).…”

Section: Introductionmentioning

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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“…Although ghrelin is an energy-deficit signal, ghrelin-null or growth hormone secretagogue receptor (GHS-R)-null mice do not display deficiencies in skeletal growth, body composition and food intake (28,29) . On high-fat diets, these knock-out animals usually do not become obese and/or insulin resistant (30,31) . The major stimulus in ghrelin secretion is fasting (32) .…”

Section: Ghrelinmentioning

confidence: 99%

Endocrine factors in the hypothalamic regulation of food intake in females: a review of the physiological roles and interactions of ghrelin, leptin, thyroid hormones, oestrogen and insulin

et al. 2011

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Controlling energy homeostasis involves modulating the desire to eat and regulating energy expenditure. The controlling machinery includes a complex interplay of hormones secreted at various peripheral endocrine endpoints, such as the gastrointestinal tract, the adipose tissue, thyroid gland and thyroid hormone-exporting organs, the ovary and the pancreas, and, last but not least, the brain itself. The peripheral hormones that are the focus of the present review (ghrelin, leptin, thyroid hormones, oestrogen and insulin) play integrated regulatory roles in and provide feedback information on the nutritional and energetic status of the body. As peripheral signals, these hormones modulate central pathways in the brain, including the hypothalamus, to influence food intake, energy expenditure and to maintain energy homeostasis. Since the growth of the literature on the role of various hormones in the regulation of energy homeostasis shows a remarkable and dynamic expansion, it is now becoming increasingly difficult to understand the individual and interactive roles of hormonal mechanisms in their true complexity. Therefore, our goal is to review, in the context of general physiology, the roles of the five bestknown peripheral trophic hormones (ghrelin, leptin, thyroid hormones, oestrogen and insulin, respectively) and discuss their interactions in the hypothalamic regulation of food intake.

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Improved insulin sensitivity and metabolic flexibility in ghrelin receptor knockout mice

Cited by 87 publications

References 23 publications

Ghrelin restores ‘lean-type’ hunger and energy expenditure profiles in morbidly obese subjects but has no effect on postgastrectomy subjects

Ghrelin restores ‘lean-type’ hunger and energy expenditure profiles in morbidly obese subjects but has no effect on postgastrectomy subjects

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

Endocrine factors in the hypothalamic regulation of food intake in females: a review of the physiological roles and interactions of ghrelin, leptin, thyroid hormones, oestrogen and insulin

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