Dataset Information

Long-acting CCK analogue NN9056 lowers food intake and body weight in obese Gottingen Minipigs.

ABSTRACT: Background/objectives: Cholecystokinin (CCK) is a regulator of appetite and energy intake in man. The aim of this study was to determine the effect of NN9056, a long-acting CCK-1 receptor-selective CCK analogue, on food intake and body weight (BW) in obese Göttingen Minipigs.

Subjects/methods: Tolerability of NN9056 and acute effects on food intake, pancreas histology, amylase and lipase levels were assessed in lean domestic pigs in doses up to 100?nmol/kg (n?=?3-4). Subsequently, obese Göttingen Minipigs were treated subcutaneously (s.c.) once daily for 13 weeks with vehicle, NN9056 low dose (regulated from 5 to 2?nmol/kg) or NN9056 high dose (10?nmol/kg) (n?=?7-8). Food intake was measured daily and BW twice weekly. At the end of the treatment period, an intravenous glucose tolerance test (IVGTT) and a 24-h exposure profile was obtained. Data are mean?±?SD.

Results: The acute studies in domestic pigs showed significant and dose-dependent effect of NN9056 on food intake, acceptable tolerability and no histopathological signs of pancreatitis. Sub-chronic treatment in obese Göttingen Minipigs was also well tolerated and accumulated food intake was significantly lower in both treated groups compared to vehicle, with no significant difference between the dose levels of NN9056 (41.8?±?12.6, 51.5?±?13.8 and 86.5?±?19.5?kg in high-dose, low-dose and vehicle groups, respectively, p?=?0.012 and p?
Conclusion: NN9056, a long-acting CCK-1 receptor-selective CCK analogue, significantly reduced food intake and BW in obese Göttingen Minipigs after once daily s.c. dosing for 13 weeks.

SUBMITTER: Christoffersen BO

PROVIDER: S-EPMC6997118 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Long-acting CCK analogue NN9056 lowers food intake and body weight in obese Göttingen Minipigs.

Christoffersen Berit Ø BØ Skyggebjerg Rikke Bjerring RB Bugge Anne A Kirk Rikke Kaae RK Vestergaard Bill B Uldam Henriette Kold HK Fels Johannes Josef JJ Pyke Charles C Sensfuss Ulrich U Sanfridson Annika A Clausen Trine Ryberg TR

International journal of obesity (2005) 20190607 2

<h4>Background/objectives</h4>Cholecystokinin (CCK) is a regulator of appetite and energy intake in man. The aim of this study was to determine the effect of NN9056, a long-acting CCK-1 receptor-selective CCK analogue, on food intake and body weight (BW) in obese Göttingen Minipigs.<h4>Subjects/methods</h4>Tolerability of NN9056 and acute effects on food intake, pancreas histology, amylase and lipase levels were assessed in lean domestic pigs in doses up to 100 nmol/kg (n = 3-4). Subsequently, o ...[more]

PMID: 31175319

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Project description:ObjectiveThe worldwide prevalence of obesity has increased to 10% in men and 15% in women and is associated with severe comorbidities such as diabetes, cancer, and cardiovascular disease. Animal models of obesity are central to experimental studies of disease mechanisms and therapeutic strategies. Diet-induced obesity (DIO) models in rodents have provided important insights into the pathophysiology of obesity and, in most instances, are the first in line for exploratory pharmacology studies. To deepen the relevance towards translation to human patients, we established a corresponding DIO model in Göttingen minipigs (GM).MethodsYoung adult female ovariectomized GM were fed a high-fat/high-energy diet for a period of 70 weeks. The ration was calculated to meet the requirements and maintain body weight (BW) of lean adult minipigs (L-GM group) or increased stepwise to achieve an obese state (DIO-GM group). Body composition, blood parameters and intravenous glucose tolerance were determined at regular intervals. A pilot chronic treatment trial with a GLP1 receptor agonist was conducted in DIO-GM. At the end of the study, the animals were necropsied and a biobank of selected tissues was established.ResultsDIO-GM developed severe subcutaneous and visceral adiposity (body fat >50% of body mass vs. 22% in L-GM), increased plasma cholesterol, triglyceride, and free fatty acid levels, insulin resistance (HOMA-IR >5 vs. 2 in L-GM), impaired glucose tolerance and increased heart rate when resting and active. However, fasting glucose concentrations stayed within normal range throughout the study. Treatment with a long-acting GLP1 receptor agonist revealed substantial reduction of food intake and body weight within four weeks, with increased drug sensitivity relative to observations in other DIO animal models. Extensive adipose tissue inflammation and adipocyte necrosis was observed in visceral, but not subcutaneous, adipose tissue of DIO-GM.ConclusionsThe Munich DIO-GM model resembles hallmarks of the human metabolic syndrome with extensive adipose tissue inflammation and adipocyte necrosis reported for the first time. DIO-GM may be used for evaluating novel treatments of obesity and associated comorbidities. They may help to identify triggers and mechanisms of fat tissue inflammation and mechanisms preventing complete metabolic decompensation despite morbid obesity.

Project description:BackgroundModel animals are valuable resources for dissecting basic aspects of the regulation of obesity and metabolism. The translatability of results relies on understanding comparative aspects of molecular pathophysiology. Several studies have shown that despite the presence of overt obesity and dyslipidemia in the pig key human pathological hepatic findings such as hepatocellular ballooning and abundant steatosis are lacking in the model.ObjectivesThe aim of this study was to elucidate why these histopathological characteristics did not occur in a high fat, fructose and cholesterol (FFC) diet-induced obese Göttingen Minipig model.MethodsHigh-throughput expression profiling of more than 90 metabolically relevant genes was performed in liver, subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) of male minipigs diet fed: standard chow (SD, n?=?7); FFC diet (n?=?14); FFC diet in streptozotocin-induced diabetic pigs (FFCDIA, n?=?8). Moreover, histopathological assessment of SAT and VAT was performed.Results12, 4 and 1 genes were highly significantly differentially expressed in liver, SAT and VAT when comparing the FFC and SD groups whereas the corresponding numbers were 15, 2, and 1 when comparing the FFCDIA and SD groups. Although the minipigs in both FFC groups developed sever obesity and dyslipidemia, the insulin-signaling pathways were not affected. Notably, four genes involved in lipid acquisition and removal, were highly deregulated in the liver: PPARG, LPL, CD36 and FABP4. These genes have been reported to play a major role in promoting hepatic steatosis in rodents and humans. Since very little macrophage-associated pro-inflammatory response was detected in the adipose tissues the expansion appears to have no adverse impact on adipose tissue metabolism.ConclusionThe study shows that morbidly obese Göttingen Minipigs are protected against many of the metabolic and hepatic abnormalities associated with obesity due to a remarkable ability to expand the adipose compartments to accommodate excess calories.

Dataset Information

Long-acting CCK analogue NN9056 lowers food intake and body weight in obese Gottingen Minipigs.

Publications

Long-acting CCK analogue NN9056 lowers food intake and body weight in obese Göttingen Minipigs.

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