Melanocortin activity in the amygdala controls appetite for dietary fat
Abstract
The amygdala is rich in melanocortin 4 receptors. Because the reduction in dietary fat intake after enterostatin is injected in the central nucleus of the amygdala (CeA) is blocked by a melanocortin 4 receptor antagonist, we investigated the role of melanocortin activity in the CeA in regulating food intake and macronutrient choice. Sprague-Dawley rats, fitted with CeA cannulas, were fed either chow, a high-fat (HF) diet, or adapted to a two-choice HF or low-fat (LF) diet. Injections of the MC4R agonist Melanotan II (MTII) in the CeA had a dose-dependent inhibitory effect on food intake that lasted for at least 24 h. This response was greater in rats fed a HF diet. The inverse agonist agouti-related protein (AgRP) and antagonist SHU-9119 increased food intake in a dose-dependent manner, with the hyperphagia lasting for 60 h. In rats adapted to a two-choice HF/LF diet, MTII decreased HF consumption but had no effect on LF consumption, resulting in a long-lasting decrease in total calorie intake (-35.5% after 24 h, P < 0.05). Total calorie intake increased in both AgRP- and SHU-9119-treated rats (32 and 109% after 24 h, respectively) as the result of increased intake of HF diet. There was no modification of LF consumption with AgRP treatment and a transient nonsignificant decrease with SHU-9119 treatment. Amygdala brain-derived neurotrophic factor expression was increased by AgRP in fed rats. These results identify the amygdala as a site of action for the melanocortin system to control food intake and dietary preferences.
Re: Melanocortins Appetite, Metabolism and Obesity
Coordination of energy use and food intake is necessary for regulation of body weight.* Today's world-wide obesity epidemic reflects a mismatch in these factors.* Our current energy requirements are little more than that required for basal metabolism and are very easily exceeded.
Appetite control is a function of the brain, more specifically, the hypothalamus.* This is a small area lying between the thalamus and pituitary, controlling the anterior segment of the pituitary and the many of the body's organs through vagus nerve stimulation.* The hypothalamus contains several clusters of neurons, commonly designated as nuclei.* Current research indicates that one of these, the arcuate nucleus, houses the appetite center.* Here we find sensors that monitor lipid and sugar levels in the circulation and others which respond to specific hormones.* Not only does the arcuate nucleus measure metabolites and hormone levels, it also coordinates metabolism through adjustment of the activities of the liver, kidneys, intestine and adipose tissue.* The hypothalamus controls appetite and coordinates this with energy utilization.* It is, therefore,* responsible for maintenance of body weight, carefully adjusting food intake to physical activity.* Loss of sensitivity to hormones and metabolites in the arcuate nucleus can lead to unbalanced energy intake and use, resulting in overweight and obesity.
The appetite center in the arcuate nucleus appears to be composed of at least two classes of neurons]
The primary neurons can be divided into two groups]
* * 1.* Those which stimulate appetite through secretion of neuropeptide* Y (NPY) and the agouti-related peptide (AgRP).
* * 2.* Neurons which depress appetite through secretion of proopiomelanocortin (POMC / Melanotan II).
Thus, a feeling of hunger can be induced through several competitive mechanisms.* Activation of the NPY/AgRP releasing neurons will increase appetite as will inhibition of the POMC-releasing neurons.* Inhibition of the first group (NPY/AgRP secreting cells) will dampen appetite as will activation of the POMC-producing neurons.
Peptide Hormones Control Eating
Several hormones are instrumental in control of the appetite center.* Some increase hunger, others reduce the urge to eat.* These have both short-term and long-term actions and are essential for control of body weight.* Several hormones were discussed]
1.* Ghrelin.* This is a peptide hormone which is released by the stomach and activates NPY/AgRP releasing neurons, thereby stimulating appetite.* Ghrelin is released from the empty stomach. Its secretion abruptly stops following food intake.
2.* PYY3-36 is a small peptide released from intestinal endocrine cells.* It inhibits "appetite-stimulating" NPY/AgRP producing neurons, thus signaling food intake and damping hunger.
Thus, hormones released directly from the digestive system steer appetite in tact with food consumption.
3.* Insulin and leptin.* Insulin release from pancreatic islets cells follows intake of both carbohydrates and proteins.* We usually assume that the brain is not dependent upon insulin for uptake and metabolism of substrates for energy metabolism.* After all, the brain has a large and relatively constant requirement for glucose as its primary energy source.* Uptake of glucose from the circulation to the CNS must not vary according to insulin levels.* However, the arcuate nucleus appears to have many properties that are in contrast to those of the rest of the brain.* Among these are receptors for protein hormones involved in the control of metabolism.* The arcuate nucleus responds to both insulin and leptin.* Insulin dampens appetite by inhibiting NPY/AgRP-secreting neurons and by activating POMC-releasing neurons.* Insulin appears to have both short-term and long-term actions and is essential in regulation of body weight.* Resistance to insulin is very often associated with obesity and the loss of insulin's regulation of metabolism as seen in diabetes type II.
Leptin levels follow body fat levels; circulating leptin levels are increased in obesity.* As is the case with insulin, leptin dampens appetite by inhibiting stimulatory neurons and stimulating inhibitory fibers.* Leptin release from adipose tissue is enhanced by insulin.* Leptin is, therefore, one of the hormones that are coupled to food consumption.* It appears that the arcuate nucleus can become leptin-resistant.* Obese persons are found with high circulating leptin levels but without response to leptin in the arcuate nucleus.* Abnormalities in leptin signaling appear to be correlated to overeating and obesity.*
Circulating Metabolites also Control Appetite Glucose.
Once again, the arcuate nucleus has some surprises for us.* We are accustomed to think that the brain has a very active glucose-uptake mechanism with a low Km.* This is required for normal brain function at all physiological levels of blood glucose.* However, the arcuate nucleus responds to swinging blood sugar levels, appetite being stimulated when blood glucose levels fall and inhibited with the high blood sugar levels encountered after a meal.* The secret to this is the presence of glucokinase (GK) in the arcuate nucleus.* In contrast to the rest of the CNS, glucokinase* accounts for 20% of the total glucose phosphorylation activity in this organ.* Because of its high Km, glucokinase activity swings in tact with normal variations in blood sugar levels.* As in pancreatic ß-cells, the GLUT2-GK system measures sugar levels and reports these as increases or decreases in ATP production.* Glucose stimulates hunger between meals and inhibits hunger after meals.
Fatty acids
Another "metabolic surprise" is that fatty acids are taken up and metabolized in the arcuate nucleus.* Again, we "know" that normal brain tissue will not take up fatty acids and that a rapid fall in blood glucose quickly leads to an energy crisis and loss of consciousness.* Fatty acids must be converted to ketone bodies before they can be taken up and metabolized by the brain.
The arcuate nucleus presents another picture.* Here, fatty acids are taken up and are converted to long-chain -fatty acyl-CoA intermediates (LCFACoA).* These are formed from both circulating fatty acids and from fatty acids produced in the arcuate nucleus.* Circulating levels of fatty acids are an excellent signal of the total metabolic situation, and the LCFACoA formed in the arcuate nucleus dampen appetite and reduce food intake.*
Central control of insulin sensitivity (insulin resistance)
Type 2 diabetes is characterized of two processes, a slowly developing resistance to insulin signaling and a compensatory increase in beta cell release of the hormone.* With time, the beta cells no longer produce enough insulin to maintain control of metabolism and type 2 diabetes results.* While the underlying cause of insulin resistance is unknown, there is a striking correlation between obesity, increased plasma lipids and resistance.* Today's treatment of type 2 diabetes aims at reducing body weight and blood lipids through dieting,* increasing hepatic insulin sensitivity with metformin and increasing beta cell insulin release through various medications.* For many patients, this results in a slowing of the progress from prediabetes to diabetes, but the end result is often that patients must go over to use of insulin.
This section of MedBio has shown data indicating that several central neural pathways are involved in control of metabolism.* Recently (November 2007) an international group has clearly shown that central receptors for serotonin play a major role in glucose homeostasis.* Thus far, their work has been limited to experiments in obese mice.* They have demonstrated that small doses of a known classical serotonin agonist, metachlorophenylpiperazine (mCPP),* markedly lowed plasma insulin levels and increased insulin sensitivity without affecting food intake, body weight or fat mass.* The downstream target of the involved serotonin receptor appeared to be melanocortin-4 receptors, found in the same brain area described above (the arcuate nucleus of the hypothalamus).* The serotonin effects on insulin resistance were coupled to sympathetic nervous stimulation as are the CNS actions of the insulin, leptin, ghrelin and PYY 3-31.
Self-control of appetite
The signals and control elements involved in management of appetite and body weight have evolved over many 100,000 years.* They are based on the amount of physical work needed to survive under “primitive” conditions.* That is, we have evolved in a time without machines and energy-saving appliances.* It is estimated that a normal total energy expenditure for both sexes was about 3000 kcal/day until about 100 years ago.* Our basal metabolism requires approximately 1500-1600 kcal daily.* Food intake amounting to circa 1500 kcal was necessary to balance energy intake and output.* Today’s daily physical effort requires about 500-1000 kcalories giving a total energy need of between 1800-2500 kcalories.* That is, the difference between basal metabolism and today’s total energy use is much smaller than that which was common 100 years ago.* Maintaining an appropriate balance between energy requirements and food intake becomes difficult as more and more precise control elements are required to measure small differences in “input and output”.* And, evolution of control takes time!* Our life style has changed faster that evolution can adjust our bodies to “fast food” and “energy-saving appliances”.* We can determine to eat a little more of that “good food” even though our “appetite center” says “stop”.* We can choose to reduce physical work by using self-powered machines.* And we can choose to just sit and watch TV or a PC screen.* Is this the basis for the global obesity epidemic we now face?* Are demands on our “appetite control center” too extensive?* * One factor that complicates this is that the brain seems to defend our maximal weight.* That is, appetite seems to be partially driven by an urge to maintain maximal weight.* Appetite increases when we try to reduce food intake.* At the same time, central elements reduce the basal metabolic rate in an effort to maintain balance between “input and output”.* It is difficult to lose weight and maintain this reduction over time!
"The key point is that understanding overeating and obesity involves not only understanding the hypothalamic feeding centers and how they respond to fats, carbohydrates and proteins..., but how those centers are driven by the brain mechanisms underlying the flavors of those foods and the desire to consume them."*
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