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Food intake is regulated by both appetite and orosensory reward systems. Appetite systems stimulate or reduce hunger, while orosensory reward motivates consumption of high fat sweet foods, resulting in food enjoyment. The majority of advanced cancer patients suffer from malnutrition and wasting, which may be caused by a loss of appetite due to physiological changes or a hindered orosensory reward system due to taste and smell (chemosensory) changes or both. Orosensory reward systems were hypothesized to be impaired in advanced cancer. To understand the influence of chemosensory alterations on food intake and enjoyment, the nature (intensity) of chemosensory alterations in cancer patients and their relationship with ingestive behaviour and quality of life (QOL) were investigated (study 1). Advanced cancer patients (n=192) more frequently self-reported tastes and odours to be heightened rather than diminished (p=0.035). Patients with perceived chemosensory alterations had poorer QOL (p=0.0176) and lower caloric intake (p=0.0018) compared to patients with no alterations. Cannabinoids (e.g. -9-tetrahydrocannabinol, -9-THC) increase food intake by stimulating both appetite and orosensory reward systems as well as potentially enhancing chemosensory function. To palliate chemosensory alterations and poor appetite, advanced cancer patients (n=21, study 2) with these symptoms were randomized to receive either -9-THC (2.5mg) or placebo oral capsules twice daily for 18 days. Compared to patients receiving placebo, -9-THC-treated patients reported that food tasted better (p=0.04), they had improved chemosensory perception (p=0.026), increased preference and intake of high protein foods (p=0.008), and improved appetite (p=0.05), quality of sleep (p= 0.025), and relaxation (p= 0.045). Like cancer patients, tumour-bearing rats appeared to experience a loss of orosensory reward, showing tumour-associated anorexia when fed a rewarding diet to the same degree as on a usual diet (study 3). -9-THC significantly increased caloric intake compared to vehicle for both tumour-bearing (p=0.0146) and healthy rats (p=0.0004), suggesting endocannabinoid-mediated appetite systems are functioning in this tumour model. The findings of this thesis suggest orosensory reward systems to be impaired in advanced cancer, decreasing the liking and motivation to eat. -9-THC treatment may help to palliate perceived chemosensory alterations and loss of appetite and food enjoyment in advanced cancer. / Food Science and Technology

La Sclérose Latérale Amyotrophique (SLA) est une maladie neurodégénérative due à la dégénérescence des motoneurones supérieurs et inférieurs. La perte des neurones moteurs entraine une atrophie puis une paralysie progressive des muscles. En plus de la perte musculaire, une perte de poids est importante chez les patients SLA. Ce symptôme apparaît avant les premiers symptômes moteurs et est corrélé avec la survie. Ce défaut du métabolisme énergétique est en partie dû à un hypermétabolisme associé à des problèmes de prise alimentaire. L’hypothalamus est la partie du cerveau contrôlant l’ensemble du métabolisme énergétique. L’objectif de ma thèse a été de caractériser les altérations hypothalamiques dans la SLA. Nous avons tout d’abord mis en évidence une anomalie du système mélanocortine de l’hypothalamus, et montré que cette anomalie était associée à des modifications du comportement alimentaire. Ensuite, nos travaux ont mis en évidence une atrophie de la partie postérieure de l’hypothalamus, comprenant l’aire hypothalamique latérale (LHA), des patients SLA, corrélée à la perte de poids. Finalement, nous démontré que les neurones produisant le MCH, situés dans le LHA, sont atteints dans la SLA et qu’une complémentation en MCH empêche la perte de poids dans un modèle animal de SLA. / Amyotrophic Lateral Sclerosis (ALS) is a major neurodegenerative disease characterised by a loss of upper and lower motor neurons. The loss of motor neurons leads to muscle atrophy and paralysis. Besides motor loss, weight loss is important in ALS patients. This symptom appears before first muscular symptoms and is correlated with survival. This defect of energetic metabolism is partially due to hypermetabolism associated with food intake problems. Hypothalamus is the part of brain controlling the energetic metabolism. The aim of my Ph.D. was to characterise hypothalamic alterations in ALS. First, we have shown a default in the melanocortin system of hypothalamus, and shown that this melanocortin defect correlates with alterations in food intake behaviour. Second, we demonstrated the existence of hypothalamic atrophy in ALS patients in the posterior part of the hypothalamus, including the lateral hypothalamic area (LHA). This atrophy was correlated with weight loss. Finally, we observed that hypothalamic MCH neurons, located in the LHA, are affected in ALS, and that MCH complementation rescues weight loss in a mouse model of ALS.