Metabolic syndrome and extensive adipose tissue inflammation in morbidly obese Göttingen minipigs

Abstract

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.

The role of the microbiota in sedentary lifestyle disorders and ageing: lessons from the animal kingdom

“…This is also observed for hypertension, which is now the most common disease globally . Recently, however, a mini pig model has been described which more closely described the human pathogenesis of metabolic syndrome, inclusive of adipose tissue inflammation and adipocyte necrosis, not see in other rodent models . This is encouraging, but still has a fundamental flaw, in that captivity will alter its co‐evolved commensal microbiome, as has been observed for primates.…”

Lipid distribution patterns of nine commercial fish in Thailand

“…In Nile tilapia and red tilapia, we found oil red O stained in retroperitoneal fat. This has, to the best of our knowledge, not been reported previously in any fish, although the retroperitoneal fat is associated with metabolic diseases in mammalian species (Hung et al, ; Renner et al, ). Lipid content of skeletal muscle in the two tilapia species was lower than those of other fish (see Table ).…”

Multi-Omics Insights into Functional Alterations of the Liver in Insulin-Deficient Diabetes Mellitus

“…Nevertheless, there was no histological evidence for fatty liver disease in MIDY pigs (data not shown), although up to 40% of adult patients with type diabetes were reported to have nonalcoholic fatty liver disease (NAFLD) (reviewed in [69]). This discrepancy is most likely due to the natural resistance of pigs against fatty liver disease, even in morbid obesity [70].…”