The CB1 Receptor as the Cornerstone of Exostasis Pier Vincenzo Piazza, Daniela Cota, Giovanni Marsicano  Neuron  Volume 93, Issue 6, Pages 1252-1274 (March 2017) DOI: 10.1016/j.neuron.2017.02.002 Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 1 Evolution of Food Sources over the Time For approximately four million years, humans have evolved in an environment where foraging supplies were very variable. Therefore, during the largest period of the evolution of our species, we had no control over food availability and were unable to store food and prevent food shortages. At around 10,000 BC, farming began, which stabilized the energy sources. One hundred years ago, the introduction of the fridge and other technological advances finally allowed producing and preserving food in large amounts, provoking a shift from “stable” to “supra-stable” environmental conditions. However, the supra-stable condition of modern time (100 years) is virtually nonexistent in an evolutionary time frame. Neuron 2017 93, 1252-1274DOI: (10.1016/j.neuron.2017.02.002) Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 2 Endostasis and Exostasis: Two Equally Important Homeostatic Functions Increase the Chance of Survival Eating behavior and energy accumulation is governed by two homeostatic systems. The endostatic system pushes the individual to eat to compensate for a decrease in the level of fuel in the organism to maintain an ideal energy level. The exostatic system (previously described has non-homeostatic or uncompensated) pushes the individual to eat as a function of food availability allowing increased energy storage to overcome future decreases in energy source availability. (A–C) The “Homo Endostaticus,” in which the endostatic system is prevalent, by eating as a function of internal needs, will have a greater chance of surviving during periods of plenty (A and C), but will be disadvantaged during periods of scarce food availability (B). Conversely, The “Homo Exostaticus,” in which the exostatic system is prevalent, by eating every time food is available, will have greater chances of survival during future periods of scarce energy sources (B), but will over eat (A) and will be at risk of developing obesity and associated metabolic disorders when food is abundantly available, as it happens presently (C). Neuron 2017 93, 1252-1274DOI: (10.1016/j.neuron.2017.02.002) Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 3 The Endocannabinoid System Is the Prototypical Exostatic System By exerting coordinated actions at target tissues, CB1 receptor activation favors food intake and energy storage. By acting on the central and the autonomous nervous system, CB1 receptor activation increases food intake while inhibiting energy expenditure and the use of lipids as fuel substrates in peripheral organs. CB1 receptors also modulate olfaction and taste responses and favor fat preference and intake through action on the gastrointestinal tract. Finally, by acting on the adipose tissue, the skeletal muscle, the pancreas, and the liver, CB1 receptors exert a multi-organ action directed toward the increase of energy storage capacity and fat accumulation in the organism. In particular by (1) increasing at the same time insulin and glucose levels, key humoral conditions to promote lipidogenesis in the liver and by (2) facilitating the uptake of lipids by adipocytes, the limiting step in lipid storage. BAT, brown adipose tissue; EE, energy expenditure; SNS, sympathetic nervous system; WAT, white adipose tissue. Neuron 2017 93, 1252-1274DOI: (10.1016/j.neuron.2017.02.002) Copyright © 2017 Elsevier Inc. Terms and Conditions