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Liraglutide pharmacotherapy reduces body weight and improves glycaemic control in juvenile obese/hyperglycaemic male and female rats.

ABSTRACT: AIMS:To examine whether the glucagon-like peptide-1 receptor agonist liraglutide could be used in juvenile male and female rats as an anti-obesity/diabetic pharmaceutical to prevent not only adolescent obesity/hyperglycaemia, but also early-adult onset obesity. MATERIAL AND METHODS:Pregnant dams were fed either standard chow or a high-fat, high-sucrose diet (HFSD) from gestational day 2, throughout pregnancy and lactation. Offspring were weaned onto the respective maternal diet. Juveniles received daily subcutaneous injection of liraglutide (50??g/kg, from postnatal day [PND]30 to PND40 and 200??g/kg from PND40 to PND60) or vehicle. Food intake, body weight and glycaemic levels were evaluated across the experimental period. RESULTS:Chronic liraglutide administration in juveniles prevented body weight gain in males and retained a normoglycaemic profile in both male and female rats. CONCLUSION:These preclinical data suggest that maternal and early-life consumption of an HFSD increases caloric intake, body weight gain and hyperglycaemia, a collective set of unwanted metabolic effects that appear to be treatable in juveniles with liraglutide pharmacotherapy intervention.

SUBMITTER: Liberini CG

PROVIDER: S-EPMC7274726 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Liraglutide pharmacotherapy reduces body weight and improves glycaemic control in juvenile obese/hyperglycaemic male and female rats.

Liberini Claudia G CG Lhamo Rinzin R Ghidewon Misgana M Ling Tyler T Juntereal Nina N Chen Jack J Cao Anh A Stein Lauren M LM Hayes Matthew R MR

Diabetes, obesity & metabolism 20181221 4

<h4>Aims</h4>To examine whether the glucagon-like peptide-1 receptor agonist liraglutide could be used in juvenile male and female rats as an anti-obesity/diabetic pharmaceutical to prevent not only adolescent obesity/hyperglycaemia, but also early-adult onset obesity.<h4>Material and methods</h4>Pregnant dams were fed either standard chow or a high-fat, high-sucrose diet (HFSD) from gestational day 2, throughout pregnancy and lactation. Offspring were weaned onto the respective maternal diet. J ...[more]

PMID: 30456866

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Project description:Radiotherapy is an effective tool in the treatment of pediatric malignancies but it is associated with adverse side effects, both short- and long-term. One common long-term side effect after cranial radiotherapy is cognitive impairment and this is, at least partly, thought to be caused by reduced hippocampal neurogenesis. Neuroinflammation and a perturbed microenvironment are thought to be important in the dysregulation of neurogenesis seen after irradiation (IR). We investigated the effects of a pre-existing, lipopolysaccharide (LPS)-induced systemic inflammation at the time of IR in both males and females. A single dose of 8 Gy to the brain of postnatal day 14 mice caused an upregulation of cytokines/chemokines (IL-1β, MIP-1β, IL-12, GM-CSF, MIP-1α, IL-17, CCL2 and KC) 6 h after IR, more so in females. Caspase-3 activity, reflecting apoptosis and possibly microglia activation, was elevated 6 h after IR. Females treated with LPS before IR showed a higher caspase-3 activity compared with males. During the chronic phase (3 months post IR), we found that LPS-induced inflammation at the time of IR aggravated the IR-induced injury in both male and female mice, as judged by reduced bromodeoxyuridine incorporation and neurogenesis (doublecortin-positive cells) in the hippocampus. At this late time point, the microglia density was increased by IR, more so in females, indicating long-term effects on the microenvironment. IR increased anxiety-related behavior in vehicle-, but not LPS-, treated animals. However, exploratory behavior was affected by IR in both vehicle- and LPS-treated mice. In conclusion, we found that LPS administration before IR of the young mouse brain aggravated the injury, as judged by reduced hippocampal neurogenesis. This supports the clinical practice to postpone radiotherapy if the patient shows signs of infection. Systemic inflammation is not always obvious, though, for example because of concurrent corticosteroid treatment, so careful monitoring of inflammation is warranted.

Project description:The GLP-1 receptor agonist liraglutide is marketed for obesity treatment where it induces body weight reduction possibly via the hypothalamus, which regulates energy homeostasis. In animal studies, acute liraglutide treatment triggers satiety, weight loss and activates thermogenesis in adipose tissue. However, the precise mechanisms how liraglutide affects in particular chronic weight loss are still under investigation.We aimed to evaluate whether chronic hypothalamic or chronic subcutaneous administration of liraglutide induces sustained weight loss through altered adipose tissue function and to what extent hypothalamic neuronal appetite regulators are involved in the liraglutide-induced weight loss in healthy lean rats on a normal diet.We continuously administered liraglutide either intrahypothalamically (10??g per day) or subcutaneously (200??g?kg-1 per day) for 28 days to lean Sprague Dawley rats (n=8 each). We assessed changes in body weight, adipose tissue mass, adipocyte size and adipose tissue volume in the abdominal region by using micro-CT. We analyzed genetic expression patterns of browning, thermogenic and adipocyte differentiation regulators in adipose tissues as well as particular neuronal appetite regulators in the hypothalamus.Intrahypothalamic liraglutide administration induced an 8% body weight reduction at day 9 compared with the control group (P<0.01) and a 7% body weight loss at day 9 compared with subcutaneous liraglutide treatment (P<0.01), supported by a significant reduction in adipose tissue mass and volume with intrahypothalamic liraglutide administration (P<0.05). Our data show that chronic intrahypothalamic liraglutide treatment triggered an 18-fold induction of the hypothalamic mc4r gene (P<0.01) accompanied by a significant increase in circulating thyroxine (T4) levels (P<0.05).Chronic intrahypothalamic liraglutide administration resulted in a profound reduction in body weight and fat mass loss most likely mediated by the hypothalamic melanocortin system rather than by adipose tissue browning or improved thermogenesis.

Project description:BackgroundMaternal obesity (MO) impairs maternal and offspring health. Mechanisms and interventions to prevent adverse maternal and offspring outcomes need to be determined. Human studies are confounded by socio-economic status providing the rationale for controlled animal data on effects of maternal exercise (MEx) intervention on maternal (F0) and offspring (F1) outcomes in MO.HypothesisMO produces metabolic and endocrine dysfunction, increases maternal and offspring glucocorticoid exposure, oxidative stress and adverse offspring outcomes by postnatal day (PND) 36. MEx in part prevents these outcomes.MethodsF0 female rats ate either control or obesogenic diet from weaning through lactation. Half of each group wheel ran (from day 90 of life through pregnancy beginning day 120) providing four groups (n=8/group)--(i) controls, (ii) obese, (iii) exercised controls and (iv) exercised obese. After weaning, PND 21, F1 offspring ate a control diet. Metabolic parameters of F0 prepregnancy and end of lactation and F1 offspring at PND 36 were analyzed.ResultsExercise did not change maternal weight. Before breeding, MO elevated F0 glucose, insulin, triglycerides, cholesterol, leptin, fat and oxidative stress. Exercise completely prevented the triglyceride rise and partially increases glucose, insulin, cholesterol and oxidative stress. MO decreased fertility, recovered by exercise. At the end of lactation, exercise returned all metabolic variables except leptin to control levels. Exercise partially prevented MO elevated corticosterone. F1 offspring weights were similar at birth. At PND 36, MO increased F1 male but not female offspring leptin, triglycerides and fat mass. In controls, exercise reduced male and female offspring glucose, prevented the offspring leptin increase and partially the triglyceride rise.ConclusionsMEx before and during pregnancy has beneficial effects on the maternal and offspring metabolism and endocrine function occurring with no weight change in mothers and offspring indicating the importance of body composition rather than weight in evaluations of metabolic status.

Dataset Information

Liraglutide pharmacotherapy reduces body weight and improves glycaemic control in juvenile obese/hyperglycaemic male and female rats.

Publications

Liraglutide pharmacotherapy reduces body weight and improves glycaemic control in juvenile obese/hyperglycaemic male and female rats.

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