Defective adaptive thermogenesis contributes to metabolic syndrome and liver steatosis in obese mice.
Fatty liver diseases are complications of the metabolic syndrome associated with obesity, insulin resistance and low grade inflammation. Our aim was to uncover mechanisms contributing to hepatic complications in this setting. We used foz/foz mice prone to obesity, insulin resistance and progressive fibrosing non-alcoholic steatohepatitis (NASH). Foz/foz mice are hyperphagic but wild-type (WT)-matched calorie intake failed to protect against obesity, adipose inflammation and glucose intolerance. Obese foz/foz mice had similar physical activity level but reduced energy expenditure. Thermogenic adaptation to high-fat diet (HFD) or to cold exposure was severely impaired in foz/foz mice compared with HFD-fed WT littermates due to lower sympathetic tone in their brown adipose tissue (BAT). Intermittent cold exposure (ICE) restored BAT function and thereby improved glucose tolerance, decreased fat mass and liver steatosis. We conclude that failure of BAT adaptation drives the metabolic complications of obesity in foz/foz mice, including development of liver steatosis. Induction of endogenous BAT function had a significant therapeutic impact on obesity, glucose tolerance and liver complications and is a potential new avenue for therapy of non-alcoholic fatty liver disease (NAFLD).
Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, 1200 Brussels, Belgium.
Laurence
L
Poekes
Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, 1200 Brussels, Belgium.
Vanessa
V
Legry
Laboratory of Cellular Physiology, Institute of NeuroScience, Université catholique de Louvain, 1200 Brussels, Belgium.
Olivier
O
Schakman
Computer Assisted and Robotic Surgery, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, 1200 Brussels, Belgium.
Christine
C
Detrembleur
Molecular Imaging, Radiotherapy and Oncology Unit, Université catholique de Louvain, 1200 Brussels, Belgium.
Anne
A
Bol
Gastroenterology Unit, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, 1200 Brussels, Belgium.
Yves
Y
Horsmans
Liver Research Group, Australian National University Medical School, The Canberra Hospital, 2605 Canberra, ACT, Australia.
Geoffrey C
GC
Farrell
Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, 1200 Brussels, Belgium isabelle.leclercq@uclouvain.be.
Isabelle A
IA
Leclercq
D002001:Adipose Tissue, Brown / Q000503:physiopathology; D000818:Animals; D031204:Caloric Restriction; D003080:Cold Temperature; D004195:Disease Models, Animal; D002149:Energy Intake; D004734:Energy Metabolism / Q000502:physiology; D018149:Glucose Intolerance / Q000503:physiopathology; D008297:Male; D024821:Metabolic Syndrome / Q000209:etiology / Q000503:physiopathology*; D008820:Mice, Obese; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology / Q000503:physiopathology*; D009765:Obesity / Q000150:complications / Q000503:physiopathology*; D010101:Oxygen Consumption / Q000502:physiology; D010805:Physical Conditioning, Animal / Q000502:physiology; D022722:Thermogenesis / Q000502:physiology*
brown adipose tissue; energy expenditure; metabolic syndrome; non-alcoholic fatty liver disease; obesity; thermogenesis