Neuroregulation of Appetite: Paleo Nutrition Supports Homeostasis
of Macronutrients and Energy Balance.
David C. Pendergrass, Ph.D. University of Kansas, Overland Park, KS
INTRODUCTION
DISCUSSION
The 2010 Dietary Guidelines for Americans is the current standard for the American diet as endorsed by both the
American Dietetic Association and the American Diabetes Association. This diet advocates a calories in/calories out
nutrition plan by ingestion of whole grains, vegetables, fruits, low fat milk and cheese (or soy), mono- and polyunsatured
oils, and meats. Furthermore, the Guidelines suggest eating less added sugar, solid fats, refined grains and sodium.
Considering that obesity in the U.S. is greater than 34% with African- and Hispanic-Americans at greater risk than
whites, the efficacy of this diet should be questioned: Is this the best diet for human consumption?
Figure 1 depicts a schematic of CNS and peripheral controls of feeding. Hypothalamus is central to coordinating
peripheral signals and the upper cortical behavior controls. The dual hypothesis theory suggests that two centers, an
orexigenic and anorexigenic expressing poles are central to the feeding behaviors. In the paraventricular nucleus
(PVN) of the arcuate nucleus (ARC), an anorexigenic pathway receives input from the ARC nucleus centers: NPY/AgRP
and POMC/CART neurons. Perhaps needless to say, inputs from over 100 gut peptides and 30+ regulatory substrates
color the black and white versions of these two centers.
The discovery of pottery allowed grains to be stored for long periods of time in granaries. Thus, this human invention is
likely responsible for both the advent of agriculturalism as well as the rise of human populations because calories
became so much more readily available to everyone. From an evolutionary fitness viewpoint, the ability to reproduce,
this was a boon to humanity: We began to grow in numbers and our fitness increased! No selective pressures existed
to stop the intake of these carbohydrates stored in pottery jars. Consequently, homo sapiens is now quite dependent
upon these grains for their calories and is therefore overpopulated. Moreover, with modern, cheaper production of
grains, the caloric percent of carbohydrates in the diet has become increasingly higher. This may well be the underlying
cause of the obesity epidemic in countries using the so-called standard American diet (SAD).
The striatum, insula, orbitofrontal cortex (OFC) and amygdala/hippocampus (Hp/Amg) are central to the behavior of
feeding. Collectively these mediate: Cognitive cues to food learning, saliency of food intake, and homeostasis of
peripheral signals from gut, adipose tissue, pancreas, liver and vagal afferents. Sensory-specific satiety, as an
example, connects a cue to food satiety. Lesion of the OFC, amygdala or the connections between ameliorates this
connection. 1 The PFC in its executive function modulates of all these feeding regions. Importantly, embedded in the
inputs to this upper cortical system is the mesolimbic pathway that projects dopaminergic (DA) neurons to the nucleus
accumbens (NA) of striatum from the ventral tegmental area (VTA). This pathway mediates saliency and is a major
pathway for the so-called rewards and addiction pathways.2 Feeding behavior is now tied directly to addiction
pathways.
Several lines of evidence suggest that a hunter-gatherer diet (Paleolithic nutrition: PN) is an ideal diet. Paleolithic
nutrition advocates meat, vegetables, nuts, berries and some fruits and eschews grains, lentils, and diary as foods that
would not have been eaten by our ancestors prior to the advent of agriculture. Anthropological arguments depicting
ancestors that ate PN as compared with similar groups had significantly more bone density than that of their across-theriver grain-eating cousins. The return of urbanized aborigines, fraught with obesity and Type II diabetes, to their
ancestral home and diet saw them lose an average of 17 lbs. and amelioration of diabetes symptoms in a single month!
Several clinical studies attribute PN to be superior or equal to the diet endorsed by the American Diabetic Association
for diabetics.
The media bombardment of food cues enters into this system and is likely a major component of an obesogenic
environment. Even satiated individuals will eat a targeted food when cued.3 Food cue-potentiation appears to be a
function of the lateral hypothalamic area (LHA) [the hypothalamic orexigenic pathway], amygdala, medial PFC, OFC
with the connection between amygdala and LHA especially important. 4 Orexigenic neurons from the LHA to NA, VTA
and the autonomic nervous system (ANS) via orexin are also directly associated with drug addiction. They also induce
plastic changes in VTA that may underlie the permanence of the food cue.5 These neurons are critical for drug
preference and its reinstatement after extinction. Many genes associated with obesity seem to act on reward pathways.
6 These studies and many others strongly suggest that considerable overlap between feeding behavior and addiction
exists in these brain centers. Food as an addiction may well underlie the obesogenic environment.
Since anthropological, clinical and evolutionary lines of evidence support Paleolithic nutrition, the feeding process must
therefore be a physiological and biochemical phenomenon involving the gut and brain signals that lead to the
anorexigenic and orexigenic behaviors of feeding. Consequently, if Paleolithic nutrition is the ideal diet, then
appropriate feeding behavior should also be maintained by Paleolithic nutrition.
PFC
Modulatory
control
DA
E
Striatum
NA
E
Hp/Amg
Mesolimbic
pathway
VTA
DA
Integration of
Peripheral Signals and
STRESS
cortisol
Higher Cortical
TRH
Regions
OXY
Hypothalamus
CRH
PVN
MC3/4R
GE
GI
-
+
α-MSH
α-MSH
GI
Orexin
MCH
-
IR
-
NPY
POMC/CART Figure 1
NPY/AgRP
GE
GE
-Median Eminence
Blood Brain Barrier ARC
ObR
GI
IR
ROS
+
ObR
DVC
VMN
BDNF GI
GE GI
GE
GE
**
IR
+
Leptin
GI Tract
Ghrelin
CCK
GLP-1
PYY
OXM
Pancreas
Amylin
PP
+
IR
Liver
Glucagon
Anorexigenic signal
Orexigenic signal
+
gluconeogenesis
Figure 1: Schematic representation of Appetite Regulation
Insulin further inhibits NPY/AgRP neurons which in turn disinhibit the PVN to actuate anorexigenesis.14
Additionally, insulin directly activates PVN anorexigenesis. 13 In concert activation of POMC mRNA expression
in POMC/CART neurons of ARC which then activates the PVN to anorexigenesis.15 Insulin is indeed a very
powerful regulator of glucose metabolism.
+
CCK1/
2R
ObR
Coupled with cued gustatory rewards in an obesogenic environment, the resultant pathway could initiate the
entire hyperinsulinemic and leptinemic resistance in brain and periphery associated with obesity. Simply
removing the glucose component to prevent elevated ROS levels interrupts this positive feedback pathway.
GE GI
Area
Postremis
ObR
IR
Adipose
Insulin
Insulin receptors in ARC through activation of insulin receptor substrate (IRS) and phosphatidylinositol 3OH
kinase (PI3K) contribute to gluconeogenesis inhibition as well by activating a vagal efferent to the liver to
inhibit gluconeogenesis.12 13
In ARC neurons of both POMC/CART and NPY/AgRP, the fat and glucose metabolism converge to reactive
oxygen species (ROS). This is another integrative component of the fat and glucose metabolism. Importantly,
excess ROS results from over-oxidative states which in NPY/AgRP neurons are downregulated. This in turn
would result in increasing anorexia. In contrast, POMC/CART neurons in which ROS is over-expressed from
excessive glucose and fat metabolism would result in an orexigenic state from decreased inhibition of LHA/PFA
neurons21! This may in turn set up a positive feedback cycle that results in a persistent orexigenic state.
DMN
IR
Fig.
1 1
Figure
Ob-R
IR
Orexigenic
LHA/
PFA +
Intake of glucose activates several pathways whose homeostatic mechanism is to lower blood glucose, enter
energy production pathways, inhibit glucose production pathways, and activate anorexigenic pathways.
Glucose causes release of insulin from pancreatic β-cells, which directs glucose into hepatocytes via GLUT-4
transports. Insulin also activates hepatic phosphatases which activate glycolysis and glycogenesis and inhibit
gluconeogenesis and glycogenolysis at regulatory enzymes in each pathway. In adipocytes, insulin inhibits
lipase which inhibits lipogenesis and increases triglyceride synthesis via activation of glycerol-3-phosphate
acyltransferase.
The ARC neurons are capable of integrating glucose and fatty acid metabolism. The entry of free fatty acids
(FFA) into hypothalamic ARC neurons can be used for catabolic purposes to produce ATP. The FFA are
acylated to Coenzyme A by acyl CoA synthase to long chain fatty acid CoA (LCFA-CoA) which is carried to
mitochondria by carnitine palmitoyl transferase 1 (CPT-1) and thereby undergo β-oxidation. When glucose
enters into the neurons, it’s converted to acetyl-CoA and in excess will result in the formation of malonyl-CoA,
the precursor to LCFA-CoA production by fatty acid synthase (FAS). Malonyl-CoA, whether by catabolism of
FFA by β-oxidation or by glucose oxidation, then inhibits the CPT-1 to prevent entry of LCFA-CoA into
mitochondria. The end result is an elevated LCFA-CoA. This LCFA-CoA in turns inhibits KATP channels in
projection neurons to reduce gluconeogenesis and produce anorexia.16
E
Anorexigenic
Stress, both the psychological and the physical kind, result in changes in feeding behavior. Stress results in
downregulation of CRH in the PVN which disinhibits the anorexigenic signal. Stress levels cause changes in
most, if not all, components of the feeding behavior pathway depicted in Fig. 1. Consequently, stress results in
both failure to maintain a healthy diet and relapse in drug use. The cortisol release increases insulin, leptin
and NPY which mediate the behavioral effects.11 Stress is a major cause of relapse among abstinent drug
users and also a significant cause of failure in dieters. Indeed, the effect of stress on the sensory satiety center
is a likely mechanism for the “comfort food” phenomenon.
Leptin is released from adipose tissue in response to increasing energy storage of fats.18 Similar to insulin,
leptin binds to leptin receptors (ObR) in ARC to inhibit the NPY/AgRP neurons while activating POMC/CART
neurons18,19 and this also appears to be mediated by PI3K activation.20 Indeed, the two peptides interact at
several neuronal clusters within the ARC, PHA, LHA, DVC and NTS. Through this mechanism, hepatic
gluconeogenesis can be inhibited via the NTS and sympathetic efferents in the same manner as insulin. In
addition to the ARC interaction and the brainstem, leptin regulates glucose homeostasis from an adipose
tissue viewpoint. Subsequently, leptin resistance dysregulates glucose metabolism and alters feeding
behavior.
DA
Cuepotentiated
feeding
Obesogenic
GE
Taste, Olfaction, environment
Vision
Further evidence of gut-brain interaction is that peripheral signals act on the sensory satiety center and the
mesolimbic pathway of salience. Insulin, leptin and ghrelin act on reward centers including the mesolimbic
dopamine systems from VTA. 7-9 The anorexigenic peptides, PYY and leptin, also act on reward-related brain
areas.10
Glucose can directly excite (GE) neurons in PVN, ARC, NTS, and area postrema resulting in anorexia. In
contrast low glucose levels can activate (GI) neurons found in LHA, area postrema, PVN, and NTS.16 Indeed,
alteration in GE neurons of POMC expressing ARC neurons can result in hyperphagia.17
DA
OFC
Sensory
Specific
Insula
Satiety
Center
DISCUSSION
Y2R GLP- GHSR1
1/2R
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