Stressing the importance of choice – validity of a preclinical free-choice high-caloric diet paradigm to model behavioral, physiological, and molecular adaptations during human diet-induced obesity and metabolic dysfunction

Humans have engineered a dietary environment that has driven the global prevalence of obesity and several other chronic metabolic diseases to pandemic levels. To prevent or treat obesity and associated comorbidities, it is crucial that we understand how our dietary environment, especially in combination with a sedentary lifestyle and daily-life stress, can dysregulate energy balance and promote the development of an obese state. Substantial mechanistic insight into the maladaptive adaptations underlying caloric overconsumption and excessive weight gain has been gained by analyzing brains from rodents that were eating prefabricated nutritionally-complete pellets of high-fat diet (HFD). Although long-term consumption of HFDs induces chronic metabolic diseases, including obesity, they do not model several important characteristics of the modern-day human diet. For example, prefabricated HFDs ignore the (effects of) caloric consumption from a fluid source, do not appear to model the complex interplay in humans between stress and preference for palatable foods, and, importantly, lack any aspect of choice. Therefore, our laboratory uses an obesogenic free-choice high-fat high-sucrose (fc-HFHS) diet paradigm that provides rodents with the opportunity to choose from several diet components, varying in palatability, fluidity, texture, form, and nutritive content. Here we review recent advances in our understanding how the fc-HFHS diet disrupts peripheral metabolic processes and produces adaptations in brain circuitries that govern homeostatic and hedonic components of energy balance. Current insight suggests that the fc-HFHS diet has good construct and face validity to model human diet-induced chronic metabolic diseases, including obesity, as it combines the effects of food palatability and energy density with the stimulating effects of variety and choice. We also highlight how behavioral, physiological, and molecular adaptations might differ from those induced by prefabricated HFDs that lack an element of choice. Finally, advantages and disadvantages of using the fc-HFHS diet for preclinical studies will be discussed. This article is protected by copyright. All rights reserved.