Glucose Metabolism, Diet Composition, and the Brain

Excessive intake of saturated fat and sugar contributes to both obesity and diabetes development. Since intake of fat and sugar-sweetened beverages exceeds recommended levels worldwide, it is essential to: 1) Understand how fat and sugar intake affect glucose metabolism, and 2) Expand the knowledge on peripheral glucose control, especially regarding its central regulation. In part 1, we used a unique animal model based on free choice & access to saturated fat and/or sugar water, previously shown to induce clear hyperphagic snacking behaviour, obesity and glucose intolerance. We showed that short-term hypercaloric fat intake induced hepatic-, while the combined intake of fat and sugar induced peripheral insulin resistance. Furthermore, long-term feeding of both components impaired the early phase glucose-induced insulin response, which was associated with impaired β cell innervation. Excessive intake of saturated fat and sugar results not only in obesity, but also in unique functional changes in the striatum, a brain area classically known to regulate reward but not known to control peripheral glucose concentrations. In part 2, we discovered an unexpected role for the striatum, and especially the nucleus accumbens shell (sNAc), in the control of glucose metabolism, in which the neurotransmitters dopamine and serotonin in the sNAc exerted opposite effects on glucose metabolism. Increasing dopamine inhibited hypothalamic function, which in turn decreased hepatic glucose production. These novel findings suggest a sNAc-hypothalamus-liver-axis involved in glucose control. Together, these studies provided better understanding of how fat/sugar consumption affects glucose metabolism, and novel insights in the central regulation of glucose metabolism

Localization of fibroblast growth factor 23 protein in the rat hypothalamus

Fibroblast growth factor 23 (FGF23) is an endocrine growth factor and known to play a pivotal role in phosphate homeostasis. Interestingly, several studies point towards a function of FGF23 in the hypothalamus. FGF23 classically activates the FGF receptor 1 in the presence of the co-receptor αKlotho, of both gene expression in the brain was previously established. However, studies on gene and protein expression of FGF23 in the brain are scarce and have been inconsistent. Therefore, our aim was to localise FGF23 gene and protein expression in the rat brain with focus on the hypothalamus. Also, we investigated the protein expression of αKlotho. Adult rat brains were used to localise and visualise FGF23 and αKlotho protein in the hypothalamus by immunofluorescence labelling. Furthermore, western blots were used for assessing hypothalamic FGF23 protein expression. FGF23 gene expression was investigated by qPCR in punches of the arcuate nucleus, lateral hypothalamus, paraventricular nucleus, choroid plexus, ventrolateral thalamic nucleus and the ventromedial hypothalamus. Immunoreactivity for FGF23 and αKlotho protein was found in the hypothalamus, third ventricle lining and the choroid plexus. Western blot analysis of the hypothalamus confirmed the presence of FGF23. Gene expression of FGF23 was not detected, suggesting that the observed FGF23 protein is not brain-derived. Several FGF receptors are known to be present in the brain. Therefore, we conclude that the machinery for FGF23 signal transduction is present in several brain areas, indeed suggesting a role for FGF23 in the brain

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