Laurence Poekes

Brown adipose tissue: a potential target in the fight against obesity and the metabolic syndrome

BAT (brown adipose tissue) is the main site of thermogenesis in mammals. It is essential to ensure thermoregulation in newborns. It is also found in (some) adult humans. Its capacity to oxidize fatty acids and glucose without ATP production contributes to energy expenditure and glucose homoeostasis. Brown fat activation has thus emerged as an attractive therapeutic target for the treatment of obesity and the metabolic syndrome. In the present review, we integrate the recent advances on the metabolic role of BAT and its relation with other tissues as well as its potential contribution to fighting obesity and the metabolic syndrome.

The new‐generation pan‐peroxisome proliferator‐activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis

IVA337 is a pan‐peroxisome proliferator‐activated receptor (PPAR) agonist with moderate and well‐balanced activity on the three PPAR isoforms (α, γ, δ). PPARs are regulators of lipid metabolism, inflammation, insulin resistance, and fibrogenesis. Different single or dual PPAR agonists have been investigated for their therapeutic potential in nonalcoholic steatohepatitis (NASH), a chronic liver condition in which steatosis coexists with necroinflammation, potentially leading to liver fibrosis and cirrhosis. Clinical results have demonstrated variable improvements of histologically assessed hepatic lesions depending on the profile of the tested drug, suggesting that concomitant activation of the three PPAR isoforms would translate into a more substantial therapeutic outcome in patients with NASH. We investigated the effects of IVA337 on several preclinical models reproducing the main metabolic and hepatic features associated with NASH. These models comprised a diet‐induced obesity model (high‐fat/high‐sucrose diet); a methionine‐ and choline‐deficient diet; the foz/foz model; the CCl4‐induced liver fibrosis model (prophylactic and therapeutic) and human primary hepatic stellate cells. IVA337 normalized insulin sensitivity while controlling body weight gain, adiposity index, and serum triglyceride increases; it decreased liver steatosis, inflammation, and ballooning. IVA337 demonstrated preventive and curative effects on fibrosis in the CCl4 model and inhibited proliferation and activation of human hepatic stellate cells, the key cells driving liver fibrogenesis in NASH. Moreover, IVA337 inhibited the expression of (pro)fibrotic and inflammasome genes while increasing the expression of β‐oxidation‐related and fatty acid desaturation‐related genes in both the methionine‐ and choline‐deficient diet and the foz/foz model. For all models, IVA337 displayed an antifibrotic efficacy superior to selective PPARα, PPARδ, or PPARγ agonists. Conclusion: The therapeutic potential of IVA337 for the treatment of patients with NASH is supported by our data. (Hepatology Communications 2017;1:524–537)

Obeticholic acid improves adipose morphometry and inflammation and reduces steatosis in dietary but not metabolic obesity in mice

Nonalcoholic steatohepatitis (NASH) is the outcome of interactions between overnutrition, energy metabolism, and adipose function. Obeticholic acid (OCA) improves steatosis in patients but for unknown reasons does not resolve NASH pathology. This study therefore investigated OCA effects in Wt mice, which develop obesity with atherogenic dietary feeding, and appetite‐dysregulated, Alms1 mutant foz/foz mice fed the same diet, which develop metabolic obesity and diabetes.

Role of ciliary dysfunction in a new model of obesity and non-alcoholic steatohepatitis: the foz/foz mice

Foz/foz mice are deficient for Alms1, a ubiquitous protein essential for proper primary cilium function. They are prone to insulin resistance, obesity and diabetes, a phenotype accelerated by high-fat diet (HFD) feeding. Their unique metabolic phenotype has been linked to hyperphagia resulting from abnormal ciliary function in the central nervous system [1]. The aim of our study is to verify the dependence of the phenotype on over-feeding and to explore the role of Alms1 deficiency in intestinal energy absorption.

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).