Abstract
In recent years, the zebrafish (Danio rerio) has emerged as an alternative vertebrate model for energy homeostasis and metabolic diseases, including obesity and anorexia. It has been shown that diet-induced obesity (DIO) in zebrafish shares multiple pathophysiological features with obesity in mammals. However, a systematic and comprehensive analysis of the different pathways of energy expenditure in obese and starved fish had been missing thus far. Here, we carry out long-term ad libitum feeding (hyperphagia) and caloric restriction studies induced by low- or high-density husbandry, respectively, to investigate the impact of caloric intake on the timing of scale formation, a crucial step of postembryonic development and metamorphosis, and on somatic growth, body weight, fat storage and female reproduction. We show that all of them are positively affected by increased caloric intake, that middle-aged fish develop severe DIO, and that the body mass index (BMI) displays a strict linear correlation with whole-body triglyceride levels in adult zebrafish. Interestingly, juvenile fish are largely resistant to DIO, while BMI and triglyceride values drop in aged fish, pointing to aging-associated anorexic effects. Histological analyses further indicate that increased fat storage in white adipose tissue involves both hyperplasia and hypertrophy of adipocytes. Furthermore, in ovaries, caloric intake primarily affects the rate of oocyte growth, rather than total oocyte numbers. Finally, comparing the different pathways of energy expenditure with each other, we demonstrate that they are differentially affected by caloric restriction / high-density husbandry. In juvenile fish, scale formation is prioritized over somatic growth, while in sexually mature adults, female reproduction is prioritized over somatic growth, and somatic growth over fat storage. Our data will serve as a template for future functional studies to dissect the neuroendocrine regulators of energy homeostasis mediating differential energy allocation.
Highlights
Obesity, primarily defined as excessive or abnormal fat accumulation, is a major health problem
Because it is logistically easier especially when feeding diets other than paramecia and artemia, we applied the low density / high density approach for our long-term (2 weeks—18 months) experiments, raising and keeping fish in groups of 5, 25 or 50 individuals, while providing identical amounts of food per group
Analyses were restricted to a rather short time span, feeding young adults different amounts of artemia for just 8 weeks and not considering possible effects on reproduction. We included this important pathway of energy expenditure, and extended the analyses to younger and older ages, basically covering the entire life span of the fish and addressing known human conditions such as juvenile obesity [94] or age-related weight loss / anorexia / cachexia [95,96,97]
Summary
Primarily defined as excessive or abnormal fat accumulation, is a major health problem. The World Health Organisation estimates that more than 500 million people (aged 20 years or older) were obese in 2008, more than 10% of adults worldwide and numbers are predicted to increase even further [1,2,3]. This is especially alarming given the association between obesity and diverse pathological conditions, including type 2 diabetes, hypertension, cardiovascular disease, hyperlipidemia, non-alcoholic fatty liver, gallstones, respiratory failure and certain types of cancer [4,5,6,7], which make obesity a leading risk factor for global mortality [8,9]. Animals do not consume more food per mg body weight [21,22,23], but even learn to compensate and eat less compared to mice on standard chow [24,25,26]
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