above, there is a complicated interplay among peripheral organs and tissues and the
hindbrain, hypothalamic region, and prefrontal cortex. The brain controls food
intake by sensing internal energy-balance signals and external cues of food avail-
ability. Leptin, insulin, NPY, cortisol, and corticotropin-releasing hormone (CRH)
all interact both synergistically and in opposition in the CNS to regulate appetite
and food intake. The brain receives regulatory messages from direct nerve con-
nections, steroid hormones, peptides, and other molecules that are transported
across the blood–brain barrier and the circumventricular organs outside the blood–
brain barrier (Power and Schulkin 2009 ). Many biomarkers of hypothalamic
activity are difficult to measure in humans because they do not cross the blood–
brain barrier. Therefore, one technique used in functional magnetic resonance
imaging (fMRI) measures changes in blood oxygen levels between deoxyhe-
moglobin and oxyhemoglobin. Positron emission tomography (PET) uses
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incorporated in water to measure cerebral bloodflow, and other techniques are used
to map details of brain activity with regard to many aspects of appetite and feeding
behaviors (Dagher 2012 ; Gibson et al. 2010 ).
The brain receives extensive information from the vagus nerve. The afferent
fibers include information that infiuences satiation from the stretch receptors in the
stomach wall, and sensors in the portal blood vessels for CCK, glucose, and pH.
The vagus nerve’s input to the pancreas in response to the sight and smell of food
leads to thefirst surge of insulin in the cephalic-phase response followed by
additional insulin release when food enters the gut and when nutrients enter the
intestines. CCK from neurons in the hypothalamus acts in the CNS satiety network
(P. Doughtery 2014 ).
A number of other regulatory peptides are synthesized and secreted by nuclei in
the hypothalamus. Neuropeptide Y (NPY) is synthesized and secreted by the
hypothalamus and adipose tissue. It is upregulated in the arcuate nucleus in
response to energy deprivation and increases food intake. Leptin binds receptors in
the hypothalamus and activates signaling pathways in which high levels suppress
hunger by turning the POMC and GLP-1 neurons on and the AgRP neurons off,
stimulating anorexigenic neurons in the satiety center. Urocortin and
corticotropin-releasing (factor) hormone (CRH) type 2 receptor act synergistically
with CCK to delay gastric emptying and reduce food intake (Power and Schulkin
2009 ). Conversely, low leptin levels increase hunger by turning the POMC neurons
off and activating the NPY and AgRP neurons (Guyenet and Schwartz 2012 ; Power
and Schulkin 2009 ).
A family of neuropeptides including urocortin and corticotropin-releasing (fac-
tor) hormone (CRH) synthesized by neurons in the hypothalamic paraventricular
nuclei serve neurotransmitter/neuromodulator roles in the CNS. CRH is widely
distributed throughout the body and stimulates adrenocorticotropic hormone
(ACTH) release activating the hypothalamic–pituitary–adrenal axis. These potent
peptides are also associated with fear or distress (Power and Schulkin 2009 ).
The hormones, enzymes, neurotransmitters, and other peptides discussed above
are biomarkers of appetite and feeding behaviors that have been well characterized
in animal and human studies. However, these invisible, internal signals of hunger,
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