Metabolic syndrome and extensive adipose tissue inflammation in morbidly obese Göttingen minipigs
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Metabolic syndrome and extensive adipose tissue inflammation in morbidly obese Göttingen minipigs. / Renner, S; Blutke, A; Dobenecker, Britta; Dhom, Georg; Müller, TD; Finan, B; Clemmensen, C; Bernau, Maren; Novak, Istvan; Rathkolb, Birgit; Senf, Steffanie; Zöls, Susanne; Roth, Mirjam; Götz, Anne; M. Hofmann, Susanne; Hrabě de Angelis, Martin; Wanke, Rüdiger; Kienzl, Ellen; M. Scholz, Armin; DiMarchi, Richard D; Ritzmann, Mathias; Tschöp, Matthias H; Wolf, Eckhard.
I: Molecular Metabolism, Bind 16, 2018.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Metabolic syndrome and extensive adipose tissue inflammation in morbidly obese Göttingen minipigs
AU - Renner, S
AU - Blutke, A
AU - Dobenecker, Britta
AU - Dhom, Georg
AU - Müller, TD
AU - Finan, B
AU - Clemmensen, C
AU - Bernau, Maren
AU - Novak, Istvan
AU - Rathkolb, Birgit
AU - Senf, Steffanie
AU - Zöls, Susanne
AU - Roth, Mirjam
AU - Götz, Anne
AU - M. Hofmann, Susanne
AU - Hrabě de Angelis, Martin
AU - Wanke, Rüdiger
AU - Kienzl, Ellen
AU - M. Scholz, Armin
AU - DiMarchi, Richard D
AU - Ritzmann, Mathias
AU - Tschöp, Matthias H
AU - Wolf, Eckhard
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
U2 - 10.1016/j.molmet.2018.06.015
DO - 10.1016/j.molmet.2018.06.015
M3 - Journal article
C2 - 30017782
VL - 16
JO - Molecular Metabolism
JF - Molecular Metabolism
SN - 2212-8778
ER -
ID: 347797893