Weight loss, insulin resistance, and study design confound results in a meta-analysis of animal models of fatty liver

Abstract

The classical drug development pipeline necessitates studies using animal models of human disease to gauge future efficacy in humans, however there is a low conversion rate from success in animals to humans. Non-alcoholic fatty liver disease (NAFLD) is a complex chronic disease without any established therapies and a major field of animal research. We performed a meta-analysis with meta-regression of 603 interventional rodent studies (10,364 animals) in NAFLD to assess which variables influenced treatment response. Weight loss and alleviation of insulin resistance were consistently associated with improvement in NAFLD. Multiple drug classes that do not affect weight in humans caused weight loss in animals. Other study design variables, such as age of animals and dietary composition, influenced the magnitude of treatment effect. Publication bias may have increased effect estimates by 37-79%. These findings help to explain the challenge of reproducibility and translation within the field of metabolism.

A Systematic Review of Animal Models of NAFLD Finds High‐Fat, High‐Fructose Diets Most Closely Resemble Human NAFLD

“…high fat, high cholesterol in C57BL/6J mice), the majority have only been used by a single study. Consideration of precise details in study design is relevant in the light of recent data that suggest that even small differences in age or diet composition may affect treatment response in animal models of NAFLD (11). Moreover, this has implications for understanding the 'reproducibility crisis' of preclinical studies (12).…”

“…Consideration of precise details in study design is relevant in the light of recent data that suggest that even small differences in age or diet composition may affect treatment response in animal models of NAFLD. ( 11 ) Moreover, this has implications for understanding the “reproducibility crisis” of preclinical studies. ( 12 ) Our results suggest that most models have never been replicated, which adds further variability in challenging in vivo studies with small effect sizes.…”

“…Models were compared for similarity based on study design. Criteria for considering two models to be the same were chosen manually given the recent finding that most outcomes in rodent models of NAFLD could be modeled in a continuous fashion ( 11 ) and included identical genetic background, sex of animals studied, age diet initiated ±1 week, kilocalories of diet from fat ±2%, weight of cholesterol in diet ±0.1%, weight of choline in diet ±0.1%, kilocalories of diet from sucrose ±2%, fructose–glucose in diet ±2% kcal (or ±2 g/L where dissolved in drinking water), age given chemical/virus/surgery ±1 week, dose of chemical ±10% (chemical‐specific), and identical route of administration of chemical. Models could be combined using variables that were not reported (e.g., studies not reporting sex, but otherwise identical models, would be considered the same).…”

“…Although this could have led us to overestimate the number of unique models, the importance of differences in genetic background in murine NAFLD phenotypes has been demonstrated by results from the Hybrid Mouse Diversity Panel (46)(47)(48)(49). At the same time, we merged unique models with minimal differences in study design, such as percentage of fat in the diet varying by 1%, where the cut-offs were chosen manually based on modal values in our data, given our recent observation that most outcomes in rodent models of NAFLD can be modelled in continuous fashion (11). At present, the significance of, for instance, 1-2% difference in dietary fat is not known.…”

“…A partial analysis of this data set has been reported elsewhere. (11) PubMed on MEDLINE, EMBASE, and the National Center for Biotechnology Information's Gene Expression Omnibus were searched for published articles of experimental rodent models of fatty liver, NAFLD, or NASH. The search was completed in January 2019.…”