Abstract
Maintenance of body weight is fundamental to maintain one’s health and to promote longevity. Nevertheless, it appears that the global obesity epidemic is still constantly increasing. Endocannabinoids (eCBs) are lipid messengers that are involved in overall body weight control by interfering with manifold central and peripheral regulatory circuits that orchestrate energy homeostasis. Initially, blocking of eCB signaling by first generation cannabinoid type 1 receptor (CB1) inverse agonists such as rimonabant revealed body weight-reducing effects in laboratory animals and men. Unfortunately, rimonabant also induced severe psychiatric side effects. At this point, it became clear that future cannabinoid research has to decipher more precisely the underlying central and peripheral mechanisms behind eCB-driven control of feeding behavior and whole body energy metabolism. Here, we will summarize the most recent advances in understanding how central eCBs interfere with circuits in the brain that control food intake and energy expenditure. Next, we will focus on how peripheral eCBs affect food digestion, nutrient transformation and energy expenditure by interfering with signaling cascades in the gastrointestinal tract, liver, pancreas, fat depots and endocrine glands. To finally outline the safe future potential of cannabinoids as medicines, our overall goal is to address the molecular, cellular and pharmacological logic behind central and peripheral eCB-mediated body weight control, and to figure out how these precise mechanistic insights are currently transferred into the development of next generation cannabinoid medicines displaying clearly improved safety profiles, such as significantly reduced side effects.
Highlights
It has evolved in human and most other species that the body weight remains relatively constant for most of the lifetime
In this article we will review the involvement of the endocannabinoid system (ECS) in body weight control both centrally and peripherally, arguing that cannabinoids and congeners represent compounds and targets of promising potential for the treatment of eating disorders and metabolic disturbances
Further evidence for the synergism between orexin/hypocretin neurons (OX) and eCBs has been found in projections from LH to ventral tegmental area (VTA), a pathway that might be relevant for the reward-related aspects of food as well: during stress, OX-A release in VTA leads to a 2-AG/cannabinoid type 1 receptor (CB1)-mediated dis-inhibition and subsequently to a reinstatement of cocaine-place-preference in previously extinguished mice [97]
Summary
It has evolved in human and most other species that the body weight remains relatively constant for most of the lifetime. Species-specific interrelations exist between body weight gain and longitudinal growth during pre-and postnatal development [2]. When occurring in physiological ranges, body weight development and maintenance are fundamental to maintain health and to promote longevity, while underweight, overweight, and obesity in childhood, adolescence and adulthood are associated with adverse health consequences throughout the life course [3]. The present body weight calculation of an individual mostly reflects the latest intake, storage and expenditure of energy. Environmental and metabolic information is received, integrated and transformed into generation of physiological behaviors such as food foraging and energy expenditure in order to provide the energy required for differentiation, growth, regeneration and maintenance of all cells, tissues and organs of the body [5]
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