Hypothalamic Regulation of Appetite

Katherine A. Simpson; Niamh M. Martin; Steve R. Bloom

Disclosures

Expert Rev Endocrinol Metab. 2008;3(5):577-592. 

In This Article

Reward Mechanisms & Hypothalamic Appetite Regulation

Reward mechanisms play a large role in appetite regulation and are thought to predominantly involve the mesolimbic system in the brain. Conditioned taste aversion (CTA) and lesioning experiments suggest the orbitofrontal cortex and amygdala are important in learning and experiencing food and its subsequent effect on food intake. Neuroimaging studies in humans have shown that pleasant and unpleasant odors activate different regions of the orbitofrontal cortex and cingulate gyrus, areas that have direct projections to the hypothalamus (Figure 1). MCH and orexin fibers in the LHA transmit and receive information from the cerebral cortex.[122] In addition, the LHA receives an inhibitory input from the shell of the nucleus accumbens, which in turn receives inputs from the prefrontal cortex.[123,124,125] Interestingly, there is high expression of CB1 receptors in the nucleus accumbens and other reward circuitry, such as the hippocampus and medial forebrain bundle. Furthermore, endocannabinoids have been found to inhibit excitatory inputs to neurons in the shell of the nucleus accumbens.[126]

Evidence to date suggests that endocannabinoids act as orexigenic signals via cannabinoid CB1 receptors in the CNS.[127] Blocking CB1 receptors inhibits food intake and causes weight loss in rodents.[128] The weight-reducing effect of CB1 antagonists (e.g., rimonabant) is accentuated in obese animals[129] and has been used in the treatment of human obesity. CB1 receptors are the most abundant G-protein-coupled receptors in the mammalian brain and are expressed in key hypothalamic areas regulating appetite, such as the PVN.[130] CB1 receptors are mainly localized to presynaptic axon terminals and activated by retrograde signaling of endocannabinoids synthesized and released by the postsynaptic neurons.

During fasting, hypothalamic endocannabinoid levels increase and subsequently decrease following refeeding.[131] Cannabinoids administered directly into the VMN increase food intake[132] and this effect is inhibited by a prior injection of a CB1 receptor antagonist via the same route. Hypothalamic endocannabinoids are purported to stimulate appetite via CB1 receptors by regulating the expression and release of anorexigenic and orexigenic neuropeptides. The mechanisms of cannabinoid-induced hyperphagia remain to be elucidated. However, evidence suggests involvement of both reward processes and established appetite modulators, such as leptin,[133] glucocorticoids[134] and melanocortins,[135] within the hypothalamus.

Recent studies support an interesting relationship between the endocannabinoid system and CART. Administration of the cannabinoid agonist HU-210 to mice results in elevated CART immunoreactivity in the ARC, DMN and the shell portion of the nucleus accumbens.[128] Interestingly, the CB1 receptor antagonist rimonabant is unable to inhibit food intake in CART-deficient mice.[128] Furthermore, mice deficient in fatty acid amide hydrolase (FAAH), the enzyme responsible for the invivo metabolism of the endocannabinoid anandamide, have reduced levels of CART immunoreactivity in several brain regions implicated in appetite control, including the ARC and DMN. When FAAH-deficient mice are treated with rimonabant, CART levels increase toward those seen in wild-type controls.[128]

There also appears to be close interaction between endocannabinoids and opioids with the finding that the orexigenic effects of an endocannabinoid were attenuated by naloxone, an opioid antagonist.[136] Interestingly, this interaction between opioids and endocannabinoids involved in feeding behavior appeared to be localized not at the mesolimbic system level but, preferentially, at the level of the PVN of the hypothalamus. This was supported by the finding that rimonabant is able to reduce morphine-induced feeding only when the opioid is directly injected into the PVN but not into the nucleus accumbens.[137]

Reward pathways utilize dopamine, opioids, serotonin and noradrenaline neuronal fibers, which connect the hindbrain and midbrain to the hypothalamus and all are known to affect appetite when injected into hypothalamic nuclei.[138,139,140,141] In addition, orexigenic NPY and anorexigenic POMC neurons in the ARC have projections throughout the brain, including the serotonergic system in the raphe nuclei and areas involved in reward, such as the amygdala.

Nicotine has also been found to affect hypothalamic neurotransmitters involved in appetite regulation. When nicotine is given to neonatal rats, it causes an increase in nicotine acetylcholine receptors in the VMN and ARC. In addition to inhibiting weight gain, nicotine administration also increases ARC NPY, AgRP and POMC mRNA expression[142] and CART gene transcript levels.[143] These effects are suppressed by the addition of a nicotinic acetylcholine receptor antagonist.[142]

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