Analysis of novel risk factors influencing control of food intake and regulation of body weight

The Problem

Background and Significance

Obesity is reaching pandemic proportions with 1.6 billion people overweight and 400 million obese worldwide [1]. In Romania alone, obesity has doubled in the past eight years [2]. Obesity is associated with metabolical syndrome, type-2 diabetes, and cardiovascular disease, but also with fatty liver disease, asthma, sleep apnea, osteoarthritis, neurodegeneration, gall bladder disease and cancer [3]. Chronic overeating plays a critical role in the development of most obesity and much of this over consumption arises from the increased palatability of the modern diet. Foods that are combinations of sugar and fat are the most preferred [4]. The percent of total daily per capita calories from added sugar and fats have increased dramatically in the past years [5]. The economic costs for treating obesity and obesity-related disease are very high with more than $125 billion a year in the USA alone [6]. Thus, understanding the factors that contribute to excessive intake is critical to reducing obesity and socio-economic burden. With large-scale attempts at increasing energy expenditure mostly unsuccessful, the necessity for therapy in combating obesity is increasingly important and understanding the mechanisms controlling meal size and energy regulation is crucial.

Hyperphagia and increased energy efficiency often accompany the persistent obesity [7],[8] with heightened orosensory and decreased peripheral sensitivity to food stimuli as main contributing factors [9],[10]. Whereas much progress has been made in identifying the homeostatic systems controlling body weight, the mechanisms through which consumption of palatable diets, rich in fats and sugars, results in heightened orosensory stimulation and diminished gut feedback signals remain poorly understood. One system that predominantly contributes to over consumption of palatable foods is the dopamine (DA) signaling pathways11 which reflects affective components of palatable food stimuli that is attributable to preference and intake [12]. For example patients chronically treated with antipsychotic drugs (D2R antagonists) have a higher risk of weight gain and obesity [13],[14]. Additionally, DA signaling is reduced in the striatum of obese individuals implicating DA in body weight control [15]. However, it is not clear whether the altered DA regulation is a cause or an effect of the altered motivational regulation or if it reflects an adaptive response to factors related to obesity. As such, the first part of the current project will determine whether over consumption of palatable foods, resulting in obesity, is a function of diet and/or the obese phenotype and whether DA system mediates this effect.

Obesity is a multifactorial disease, involving genetical, physiological, neural, metabolical, social and environmental factors [16]. Among these, recently, gut bacteria were proposed to contribute to differences in body weight and adiposity, insulin sensitivity, glucose and lipid metabolism [17]. Furthermore, alterations in gut microbiota have been associated with changes in intestinal permeability and metabolical endotoxemia that been suggested as contributing factors in systemic inflammation characteristic of obesity [18],[19]. Finally, microbiota may serve as a modulatory signal on luminal releasing chemosensing factors [20],[21] such as gut peptides controlling appetite and energy homeostasis22. Our knowledge of the role of microbiota as it relates to obesity and metabolical diseases and the underlying mechanisms is still in infancy. Therefore the second part of the current project uses an integrative and innovative approach combining high throughput metagenomic analyses with behavioural, physiological, molecular and neural approaches, employing in-vivo models, in order to decipher the mechanisms by which gut microbiota interacts with specific host signalling components and the impact of this interplay in ingestive behaviour, and pathological states such as obesity. This part of the project will focus on the role of gut microbiota on the modulation of physiological, molecular and neural signalling components implicated in regulation of energy balance in healthy and obese states using in-vivo animal models and dietary manipulations. We will use animals prone (DIO) and resistant (DR) to obesity to address the hypothesis that the microbiota acts through an integrated host signalling pathway to regulate energy storage in the host in intact, germ free and microbiota transplanted animals. Thus, this project will directly assess the contribution, dynamics, and the mechanisms of the cause/effect relationships between gut microbiota, obesity and related metabolical abnormalities.

Challenges and current limitations

Because of the multifactorial nature of obesity and the redundancy of the systems regulating energy balance some previous results are inconclusive, even controversial, with multiple confounding variables making difficult to distinguish and separate the effect from the cause or contributing factors. The proposed obese model and study design will allow us to separate the effect of the phenotype from the diet, a typical confounding effect in most studies. Furthermore, chronic exposure to dietary fat may increase preference for high caloric meals driven by their orosensory effects and a reduced sensitivity to the postabsorptive feedback signals, or both. Therefore, how exposure to dietary fats changes chemosensory input both pre- as well as and post ingestively warrants greater investigation and will be addressed in this project. Lastly, a major challenge is the inherent difficulty of teasing apart the complex interactions between microbiota, the host, and the diet, as both phenotype and diet composition have been previously shown to modulate the gut microbiota. By performing conventionalization studies using obese prone and resistant animals placed on high fat and regular diet the project will aid in overcoming this challenge.

Originality and innovation

This project applies innovative techniques spanning from behavioural, metagenomic to molecular, with the goal of identifying novel factors controlling food intake and energy regulation. This is the first proposal to employ metagenomics to study gut satiation peptides and apply that information to in vivo models. Further, to our knowledge, this is the first study characterizing the contribution of microbiota in OP and OR animals using deep sequence analysis and assess whether their respective microbiota "signature" is transferable to a germ free environment replicating the original phenotype, the behavior and associated metabolical profile. Ultimately, with the new knowledge obtained from metagenomics, the goal is to beneficially affect the host by selectively stimulating the activity of "specialized" bacteria and manipulate the microbial population to obtain the desired health benefit. The use of the obese-prone (OP) and obese-resistant (OR) rat models in delineating the effects of obesity and adiposity versus environmental factors (e.g. diets) is also novel as most studies determine associations with the obese state, but not causality. The potential rewards from this inquiry are huge. It will allow identification of new mechanisms controlling food intake and body weight that will constitute the basis for shaping prevention and therapeutical strategies with major health implications.

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