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

Haczeyni, Fahrettin; Poekes, Laurence; Wang, Shuaian; Mridha, Auvro R.; Barn, Vanessa; Haigh, W. Geoffrey; Ioannou, George N.; Yeh, Matthew M.; Leclercq, Isabelle; Teoh, Narcissus; Farrell, Geoffrey C.

doi:10.1002/oby.21701

Cited by 40 publications

(52 citation statements)

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“…Administration of obeticholic acid to mice on an atherogenic diet reduced CLS in periovarian and mesenteric adipose tissue and reduced CCR2 and CD11c mRNA expression 177 .…”

Section: Macrophage and Adipocyte Dysfunction In Obese Adipose Tissuementioning

confidence: 93%

Macrophage functions in lean and obese adipose tissue

2017

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Summary Interactions between macrophages and adipocytes influence both metabolism and inflammation. Obesity-induced changes to macrophages and adipocytes lead to chronic inflammation and insulin resistance. This paper reviews the various functions of macrophages in lean and obese adipose tissue and how obesity alters adipose tissue macrophage phenotypes. Metabolic disease and insulin resistance shift the balance between numerous pro- and anti-inflammatory regulators of macrophages and create a feed-forward loop of increasing inflammatory macrophage activation and worsening adipocyte dysfunction. This ultimately leads to adipose tissue fibrosis and diabetes. The molecular mechanisms underlying these processes have therapeutic implications for obesity, metabolic syndrome, and diabetes.

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“…Administration of obeticholic acid to mice on an atherogenic diet reduced CLS in periovarian and mesenteric adipose tissue and reduced CCR2 and CD11c mRNA expression 177 .…”

Section: Macrophage and Adipocyte Dysfunction In Obese Adipose Tissuementioning

confidence: 93%

Macrophage functions in lean and obese adipose tissue

2017

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“…Physical activity and weight loss improve insulin sensitivity and so correct the hepatic accumulation of lipotoxic lipids . However, attempts to combat hepatic lipid partitioning and promote insulin sensitization pharmacologically have been only partially effective, in the case of PPAR‐γ and farnesoid X receptor agonists, or ineffective (metformin and PPAR‐α agonists) …”

Section: Discussionmentioning

confidence: 99%

“…mRNA levels were quantified by real‐time polymerase chain‐reaction using SYBR green primers (Sigma‐Aldrich, St. Louis, MO), normalizing data to the geometric mean of β‐actin and Gapdh . Liver proteins were analyzed as described …”

Section: Methodsmentioning

confidence: 99%

“…Although NASH is a highly prevalent, serious disease, there is no currently approved drug therapy . While reversing consequences of metabolic disorder has been attempted to target NASH, the only highly effective strategies have been bariatric surgery and lifestyle changes; reducing body weight 10% reverses NASH pathology, including liver fibrosis, but is difficult to achieve . Pharmacologically, pathways targeted to improve NASH pathology are aimed at “movers” of metabolic obesity: glucagon‐like peptide 1 receptor agonists, adiponectin receptor agonists, glucokinase activity modulators, and selective peroxisome proliferator–activated receptor (PPAR) agonists …”

mentioning

confidence: 99%

“…(1,2,6,7) While reversing consequences of metabolic disorder has been attempted to target NASH, the only highly effective strategies have been bariatric surgery and lifestyle changes; reducing body weight 10% reverses NASH pathology, including liver fibrosis, but is difficult to achieve. (10)(11)(12)(13)(14)(15) Pharmacologically, pathways targeted to improve NASH pathology are aimed at "movers" of metabolic obesity: glucagon-like peptide 1 receptor agonists, adiponectin receptor agonists, glucokinase activity modulators, and selective peroxisome proliferator-activated receptor (PPAR) agonists. (14)(15)(16)(17) PPARs are a nuclear receptor superfamily of ligandinducible transcription factors (18) that induce gene expression involved in energy homeostasis, as well as inflammation pathways.…”

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confidence: 99%

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The selective peroxisome proliferator–activated receptor‐delta agonist seladelpar reverses nonalcoholic steatohepatitis pathology by abrogating lipotoxicity in diabetic obese mice

Haczeyni

Wang

Barn

et al. 2017

Hepatology Communications

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Lipotoxicity associated with insulin resistance is central to nonalcoholic steatohepatitis (NASH) pathogenesis. To date, only weight loss fully reverses NASH pathology, but mixed peroxisome proliferator–activated receptor‐alpha/delta (PPAR‐α/δ) agonists show some efficacy. Seladelpar (MBX‐8025), a selective PPAR‐δ agonist, improves atherogenic dyslipidemia. We therefore used this agent to test whether selective PPAR‐δ activation can reverse hepatic lipotoxicity and NASH in an obese, dyslipidemic, and diabetic mouse model. From weaning, female Alms1 mutant (foz/foz) mice and wild‐type littermates were fed an atherogenic diet for 16 weeks; groups (n = 8‐12) were then randomized to receive MBX‐8025 (10 mg/kg) or vehicle (1% methylcellulose) by gavage for 8 weeks. Despite minimally altering body weight, MBX‐8025 normalized hyperglycemia, hyperinsulinemia, and glucose disposal in foz/foz mice. Serum alanine aminotransferase ranged 300‐600 U/L in vehicle‐treated foz/foz mice; MBX‐8025 reduced alanine aminotransferase by 50%. In addition, MBX‐8025 normalized serum lipids and hepatic levels of free cholesterol and other lipotoxic lipids that were increased in vehicle‐treated foz/foz versus wild‐type mice. This abolished hepatocyte ballooning and apoptosis, substantially reduced steatosis and liver inflammation, and improved liver fibrosis. In vehicle‐treated foz/foz mice, the mean nonalcoholic fatty liver disease activity score was 6.9, indicating NASH; MBX‐8025 reversed NASH in all foz/foz mice (nonalcoholic fatty liver disease activity score 3.13). Conclusion: Seladelpar improves insulin sensitivity and reverses dyslipidemia and hepatic storage of lipotoxic lipids to improve NASH pathology in atherogenic diet–fed obese diabetic mice. Selective PPAR‐δ agonists act independently of weight reduction, but counter lipotoxicity related to insulin resistance, thereby providing a novel therapy for NASH. (Hepatology Communications 2017;1:663–674)

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Mouse Models of Nonalcoholic Steatohepatitis: Toward Optimization of Their Relevance to Human Nonalcoholic Steatohepatitis

et al. 2019

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Nonalcoholic steatohepatitis (NASH) arises from a variable interplay between environmental factors and geneticdeterminants that cannot be completely replicated in animals. Notwithstanding, preclinical models are needed to understand NASH pathophysiology and test mechanism-based therapies. Among several mouse models of NASH, some exhibit the key pathophysiologic as well as histopathologic criteria for human NASH, whereas others may be useful to address specific questions. Models based on overnutrition with adipose restriction/inflammation and metabolic complications, particularly insulin resistance, may be most useful to investigate critical etiopathogenic factors. In-depth pathologic description is required for all models. Some models demonstrate hepatocyte ballooning, which can be confused with microvesicular steatosis, whereas demonstration of an inflammatory infiltrate and pattern of liver fibrosis compatible with human NASH is desirable in models used for pharmacologic testing. When mice with specific genetic strains or mutations that cause overeating consume a diet enriched with fat, modest amounts of cholesterol, and/ or simple sugars ("Western diet"), they readily develop obesity with liver disease similar to human NASH, including significant fibrosis. Purely dietary models, such as high-fat/high-cholesterol, Western diet, and choline-deficient, amino acid-defined, are similarly promising. We share concern about using models without weight gain, adipose pathology, or insulin resistance/hyperinsulinemia and with inadequate documentation of liver pathology. NASH-related fibrosis is a key endpoint in trials of possible therapies. When studied for this purpose, NASH models should be reproducible and show steatohepatitis (ideally with ballooning) and at least focal bridging fibrosis, while metabolic factors/disordered lipid partitioning should contribute to etiopathogenesis. Because murine models are increasingly used to explore pharmacologic therapies for NASH, we propose a minimum set of requirements that investigators, drug companies, and journals should consider to optimize their translational value. (Hepatology 2019;69:2241-2257).

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

Cited by 40 publications

References 41 publications

Macrophage functions in lean and obese adipose tissue

Macrophage functions in lean and obese adipose tissue

The selective peroxisome proliferator–activated receptor‐delta agonist seladelpar reverses nonalcoholic steatohepatitis pathology by abrogating lipotoxicity in diabetic obese mice

Mouse Models of Nonalcoholic Steatohepatitis: Toward Optimization of Their Relevance to Human Nonalcoholic Steatohepatitis

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