"Control" laboratory rodents are metabolically morbid: why it matters

Abstract

Failure to recognize that many standard control rats and mice used in biomedical research are sedentary, obese, glucose intolerant, and on a trajectory to premature death may confound data interpretation and outcomes of human studies. Fundamental aspects of cellular physiology, vulnerability to oxidative stress, inflammation, and associated diseases are among the many biological processes affected by dietary energy intake and exercise. Although overfed sedentary rodents may be reasonable models for the study of obesity in humans, treatments shown to be efficacious in these animal models may prove ineffective or exhibit novel side effects in active, normal-weight subjects.

Fig. 1.

Differences and commonalities in gonadal and hippocampal gene expression for Sprague–Dawley rats maintained on low and high energy diets, compared with both healthy “lean” controls and standard ad libitum–fed overweight controls. (A and B) Common and unique significantly altered genes in gonadal tissue (ovaries; A) and hippocampal tissue (B) from rats on 40% caloric restriction, alternate day fasting, and a high fat/glucose diet, compared with standard ad libitum overweight controls and healthy lean controls (20% caloric restriction).

Fig. 2.

Differences and commonalities in gonadal and hippocampal gene ontology (GO) functional groups for Sprague–Dawley rats maintained on low and high energy diets, compared with both healthy “lean” controls and standard ad libitum–fed overweight controls. (A) Common and unique significantly altered GO functional groups in ovaries (A) and hippocampus (B) from rats on 40% caloric restriction, intermittent fasting, and a high fat/glucose diet, compared with standard ad libitum overweight controls and healthy lean controls (20% caloric restriction).

Fig. 3.

Differences and commonalities in gonadal and hippocampal KEGG functional pathways for Sprague–Dawley rats maintained on low and high energy diets, compared with both healthy controls and standard ad libitum–fed overweight controls. (A) Common and unique significantly altered KEGG functional pathways in ovaries (A) and hippocampus (B) from rats on 40% caloric restriction, intermittent fasting, and a high fat/glucose diet, compared with standard ad libitum overweight controls and healthy lean controls (20% caloric restriction).

Fig. 4.

Overview of various physiological differences between standard ad libitum–fed control animals and moderately fed lean animals. The percentage difference for numerous variables (gross physiology, glycemic regulatory factors, lipid regulatory factors, trophic hormones, and learning and memory) for “lean” control Sprague–Dawley rats (20% caloric restriction) compared to “standard” control Sprague–Dawley rats fed ad libitum. LDL, low density lipoprotein; HDL, high density lipoprotein; BDNF, brain-derived neurotrophic factor; and 3-HB, 3-β-hydroxybutyrate.