Jessica Stewart, MS IV
Robert Karp, MD
SUNY-Downstate Medical Center
Brooklyn, NY
Carine Lenders, MD, MS
Boston Medical Center - Boston University School of Medicine
Boston, MA
PRE-TEST
Q1. Which of the following is associated with satiation?
a. Rise in blood sugar
b. Feeling of fullness
c. GI hormone feedback
d. All of the above
Q2. Which of the following describes leptin effects on appetite?
a. Obese people have low leptin levels
b. Lean people have high leptin levels
c. Weight loss decreases leptin production
d. Weight loss increases leptin production
Q3. True or False: Short term weight reduction in an obese person prompts almost identical endocrine responses as weight loss in a lean person.
Q4. True or False: "Semistarvation is the natural state of humankind".
Q5. Explain how semistarvation affects H-P-A responses to short term
deprivation in 30 words.
OBJECTIVES
On completion of this module, residents and physicians will be able to identify
1. Elements affecting "satiety" and "appetite" in clinical practice
2. Impact of weight status (gain, stable, or lost) on appetite
3. Gastro intestinal, Neuro-peptide and Hypothalamic Pituitary Axis
modulators of appetite and weight control
4. Select syndromes associated with obesity
FACILITATOR PREPARATION
This module provides an integration of three mechanisms for weight control with commentary on the impact of both micro- and macro-nutrient intake on pathophysiology. It is based, in part, on:
- Lenders CM, Hoppin AG. (2003) Evaluation and management of Obesity. Nutrition in Pediatrics, 3rd edition. Walker WA, Watkins, JUB, Duggan C. (eds) BC Decker, Inc. Hamilton, London pp 917-34.
Resources were also drawn from the work of Ethan Allan Sims and colleagues who were among the first researchers to consider modifications in the hypothalamic Pituitary Axis in the maintenance of body weight.
An initial work showing their hypothesis was:
- Sims EA and Horton ES. Endocrine and metabolic adaptation to obesity and starvation Sims, et al, Am J Clin Nutrition 1968;21:1455-70.
- Danforth E Jr, Horton ES, O'Connell M, Sims EA, Burger AG, Ingbar SH, Braverman L, Vagenakis AG. Dietary-induced alterations in thyroid hormone metabolism during overnutrition. J Clin Invest 1970;64:1336-47.
Another older worker in obesity whose work is cited frequently is:
- Jean Mayer's Obesity (1961) published by Consumers Union.
Recent papers addressing H-P Axis function in obesity and with weight loss:
- Reinehr T, Andler W. Thyroid hormones before and after weight loss in obesity. Arch Dis Child. 2002;87;320-23.
- Kozlowska L, Rosolowska-Husscx D. Leptin, thyrotropic and thyroid hormones in obese/overweight women before and after two levels of energy reduction. Endocrine. 2004, 24:147-53.
Other references cited are found at the end of the module.
INTRODUCTION
This module addresses the unique pathophysiology of obesity recognizing that there is no inherent separation from social and environmental factor affecting weight gain. The model [Metabolism vrs. Environment] is inherently faulty. A more appropriate model is interactive [Metabolism <-> Environment].
Psychobiologic effects are real, not imagined. Consider Pavlov and his dogs. The bell rings. The dogs are fed. The bell rings. The dogs are fed. Repeat and repeat until the bell rings and the dogs are not fed. Appetite, as recognized by their salivation is stimulated. Psychobiologic phenomena provide a backdrop for the material presented herein.
Definitions
Satiation: This is all the processes that lead to the ending of a meal. This determines the size of a meal.
Satiety: This is all the processes that tell you when to eat your next meal. This determines the frequency of meals.
Satiation and satiety are often misused in the literature.
"Appetite" is not equal to "hunger." As Jean Mayer points out, Appetite is a mostly positive complex of sensations "by which one is aware of desire for and anticipation of ingestion of palatable food." By contrast, Hunger is a "…complex of unpleasant sensations, felt after prolonged deprivation, which will compel a person to seek, work or fight for immediate relief by ingestion of food." J Mayer, 1965
Thus "appetite" represents the "Macro controls" associated with perception of a need for food without necessarily being deprived. Typically individuals eat until they are comfortably full (satiation) after which they do not eat for a period of time (satiety). Not eating lead to a depression in blood sugar. Satiation centers in the hypothalamus are stimulated and there is an urge to eat. Subsequent eating causes three phenomena that feed back to reduce appetite. This theory, originating with the late (and great) Jean Meyer still holds in describing what is apparent to clinician and patient alike and is most susceptible to intervention. [See Mayer, 1955]
ELEMENTS AFFECTING APPETITE AND SATIETY
Appetite, metabolism and satiety are modulated early in life. Experience in utero, or in the first years of life, write, Barker, Lucas and Singhal, may well program infant metabolism to promote obesity mediated in part through alterations in hypothalamic-pituitary axis function at higher weight (or BMI) levels. Weight in infancy influences adult body composition such as the percent fat or lean muscle. Low weight infants accumulate more fat and less muscle later in life. Moreover the distribution of fat (truncal vs peripheral) differs - in low weight infants fat is primarily in the trunk. Mechanisms that may explain this observation are environmental feeding practices, changes is CNS appetite control or pancreatic function (insulin secretion/sensitivity), or HPA. Central obesity confers higher risk for diabetes and coronary events. Thus, whatever environmental influences, individuals become and remain obese when a set of metabolic factors creates and sustains a level of fat deposition above levels necessary for everyday function. This level is said to represent "obesity" when it affects immediate or long-term health. [see Blaxter, 1985]
Early in life, children differentially and individually regulate energy intake via internal cues. This regulation can be disturbed by caregiver influences. Birch and Fischer note that over 24 hours, children have well regulated and predictable energy intake although meal to meal variation exists. Internal cues of when to eat are well developed at a young age. Differences in self regulating correlate with child-feeding practices and the child's adiposity. Internal cues can be lost if caregivers require the child to finish his/her plate of food. Therefore the way a child is fed appears to affect children's energy balance by changing food intake patterns. Energy balance and how much to eat develops ideally when a child controls quantity and quality of foods consumed. Behavioral cues that affect eating patterns include children's predisposition to reject new foods, learned associations between taste and postprandial consequences. Both internal cues and external factors influence energy balance.
Table 1: Appetite, Satiation, and Satiety: Examples of internal signals associated with appetite and satiety.
1. Initiation of a meal (appetite):
a. Ghrelin is high
b. Glucose is lower than baseline.
2. End of a meal (satiation):
a. Stomach is distended and nutrients are present;
b. GI peptides are active;
c. Adipocyte hormones are released.
3. Interval of time between meals (satiety):
a. External cues
b. Adipocyte hormones and CNS pathway
4. Cellular metabolism
a. One enzyme in cells senses energy balance - AMP-kinase.
TEACHING COMMENT: Both external and internal cues will affect feeling of appetite and satiety. AMP-kinase turns on energy generating processes and turns off energy consuming processes in the cell. Nutritional deficiency activates this enzyme. Its effect in skeletal muscle, liver and fat is to increase metabolism. In the hypothalamus, its effect is to increase food intake. Further understanding of this dual function AMP-kinase is underway.
The information in Table 1 has several potential ramifications:
1. Small frequent meals may lead to better appetite control than infrequent large meals.
2. High fiber low sugar (low glycemic index) meals may provide better satiety.
3. Some fat in the diet may be needed to suppress appetite.
Let's focus on implication #2. The Glycemic Index (GI) is a ratio calculated from the area under the glucose tolerance curve of a standard 50-gram glucose challenge (the denominator) and a similar curve formed from the consumption of a specific food (the numerator). The effect of food on the glucose area under the curve is illustrated below.
FIGURE 1: Glycemic Index Curve
TEACHING CAPTION: Potatoes, for example, contain quickly absorbed starch. The area under the blood glucose vs. time curve for potatoes contains almost the same area as a standard glucose tolerance curve. Thus, the Glycemic Index is high for potatoes. By contrast, meals containing wheat bran (cereal fiber and protein) or other fibers tend to have slowly absorbed sugar, less area under the blood glucose curve, and a low GI.
Recent studies provide data suggesting that a freely chosen low GI diet may be more effective in promoting and sustaining weight loss in obese children than controlled low calorie dieting. Recently, bran cereal meals taken in the morning were found to promote less food intake at lunch
without regard to nutritional status of the children. (See Ludwig DS, 2002)
Thus types of foods in the diet and frequency of the diet may affect weight control. Further
comments on behavioral controls are found in Part 3 Section 8 of the Teacher's guide.
Obesity is the result of low energy expenditure or high energy consumption. An important concern for every clinician and every patient is whether the patient has a recognizable condition - such as an endocrine problem or a syndrome. (See Table 2) If this is the case, obesity is the result of heredity traits favoring storage of energy. Alternatively, the patient may have a socio-economic or mental health background favoring inactivity and unhealthy eating. In this case, psychiatric conditions or poverty can play a role.
GI, NEUROPEPTIDES AND HPA MODULATORS OF APPETITE AND WEIGHT
We address four metabolic control mechanisms on body weight maintenance - 1) gastrointestinal peptides, 2) adiposity hormones, 3) CNS pathways including HPA, and 4) cellular metabolism - to describe the pathophysiology of obesity. We will explain each of the control mechanisms and use a case study to show how they might interact.
A Glossary of Terms and Definitions:
The presentation that follows contains terms that are not in common use in clinical pediatrics. This listing gives names, abbreviations and:
Pro-opiomelanocortin = POMC
Agouti-related peptide = AGRP
Neuropeptide Y = NPY
Cocaine and amphetamine
related transcript = CART
Peptide YY = PYY
Cholecystekinine = CCK
Alpha-melanocyte-stimulating hormone = MSH
Melanocortin 4 receptor = MC4-R
Melanin-containing hormone = MCH
GI Peptide control of appetite
A principle appetite stimulating hormone is "Ghrelin." This hormone in the pathway to appetite is primarily secreted from the stomach but also from the brain when body food stores are low. Its receptors are widespread throughout the body. Similarly its actions have multiple biological effects.
For example, ghrelin stimulates ACTH, prolactin, and growth hormone release through its action on the pituitary. The name reflects it Growth Hormone RELeasing effects.
FIGURE 2: How Ghrelin stimulates appetite
TEACHING CAPTION: Ghrelin stimulates appetite through both central and peripheral actions.
Before meals, ghrelin levels increase and after meals levels decrease. The rise before eating may suggest a cue for initiating a meal. Derangement of ghrelin secretion is associated with obesity. Paradoxically, overweight children have lower levels of ghrelin before meals compared to normal weight children. (see Bacha)
GI peptide control of satiation
Q. What happens to GI peptides after a meal?"
A. PYY, CCK, GLP-1 among others are secreted. These suppress appetite.
1. Cholecystekinin (CCK)
CCK is a hormone produced in the gut and acts peripherally at the GI tract and centrally in the brain. During a meal, CCK acts via the parasympathetic nervous system to decrease food intake. It cannot enter the brain due to the blood brain barrier. CCK binds receptors on the peripheral vagus nerve and this signals satiation indirectly. CCK also stimulates leptin secretion to synergistically reduce food intake. In the GI tract, CCK increases absorption by slowing stomach emptying and increases pancreatic secretions for digestion of a meal. These actions promote digestion and curb food intake.
2. Peptide YY (PYY)
PYY is secreted after meals from the gut. The amount of PYY is proportional to the energy content of the meal. More PYY is secreted for lipids than carbohydrates and least is secreted for proteins. PYY also delays stomach emptying thereby contributing to the ileal break. PYY decreases food intake through its actions in the arcuate nucleus pathway. PYY indirectly suppresses appetite. NPY is inhibited and POMC neurons are stimulated without PYY entering the neural system, per se. In obese individuals PYY levels are low. This suggests that PYY does not suppress their appetite as much as a normal weight individual.
3. Glucagon-like peptide 1 (GLP-1)
GLP-1 is a satiation gut hormone that is produced in the small intestine and colon. Its precursor protein also makes other GI peptides - oxyntomodulin, PYY and CCK. Nutrients, especially fat and carbohydrates, stimulate GLP-1 secretion both directly (contact) and indirectly (neuro-hormonal signaling). GLP-1 has receptors at gut, pancreas, brainstem, hypothalamus and vagus nerve. GLP-1 acts as an ileal break. Ileal break is the set of feedback signals that inhibit stomach emptying and motility. Intestinal signals activate the ileal break to end a meal and to decrease the rate of nutrients entering the blood. GLP-1 also stimulates glucose dependent insulin release from the pancreas - increasing after-meal insulin release - and pancreatic beta cell growth. Similarly, GLP-1 inhibits glucagon secretion and decreases appetite.
In experiments, GLP-1 given to humans and animals peripherally inhibits appetite. GLP-1 is also important in glucose homeostasis in type 2 diabetes. It is manufactured as exenatide, one antidiabetic medication.
In obese patients, GLP-1 secretion is decreased compared to normal weights individuals. Upon weight loss, GLP-1 secretion normalizes.
Influences of long acting fat hormones on appetite
Adiposity signals are hormones that are secreted in direct proportion to body fat. Their secretion is increased during meals. They inform the brain about insufficiency and excess body fat. The two best known are insulin and leptin. Others are amylin and adiponectin. Adipose tissue is now viewed as a metabolically active as well as endocrine organ. It secretes many proteins and has a role in energy homeostasis. Furthermore, its proteins affect obesity related complications such as insulin resistance and atherosclerosis (via leptin, adiponectin, TNF-alpha).
A major agent affecting regulation of body weight is the hormone leptin. Leptin is a regulator of body fat and it is primarily produced in adipose tissue. The more adipose tissue there is the more leptin is secreted. However, the primary role of leptin is to signal insufficiency not excess of fat. Although obesity is characterized by high leptin, leptin falls with weight loss and decreased energy expenditure. Of note is the importance of dynamic as well as static measures of leptin.
FIGURE 3
TEACHING CAPTION: (top figure) Leptin secretion is at a high but steady level. (middle figure) Leptin level is at a low but steady level. (bottom figure) Secretion of leptin is greatly reduced when the overweight child or adult looses weight. Change in leptin level is more important than leptin level, per se.
Leptin acts on the ventromedial hypothalamus by activating a network of regulatory neuropeptides present in the hypothalamus. In addition, as fat accumulates, leptin stimulates counter regulatory mechanisms to protect against lipid toxicity within cells. Increased fat leads to increased leptin level which leads to decreased lipogenesis. In other words, leptin's action results in resistance to the activities of insulin - or insulin resistance.
Figure 4:
TEACHING CAPTION: The ventromedial hypothalamus holds the satiation center of the central nervous system regulating appetite directly. Leptin levels affect energy expenditure indirectly. It is through the activation of brain pathways that leptin carries out its actions.
The following Q and A walks through the impact of change in leptin level.
Q. How does leptin affect metabolism?
A. The person with high, maintained levels of leptin will have a decrease in appetite, and increase in energy expenditure. High leptin levels increase the amount of energy spent while exercising and
at rest. By contrast, persons with decreasing leptin tend to be preoccupied with food. Leptin deficiency or absence of leptin receptors results in hyperphagia and decreased thermogenesis and physical activity. Body fat is thus increased.
Q. What physiologic effects follow?
A. Leptin influences the following in the arcuate nucleus:
1) pro-opiomelanocortin (POMC)
2) Agouti-related peptide (AGRP)
3) Neuropeptide Y (NPY) and
4) Cocaine and amphetamine related transcript (CART).
Leptin positively stimulates POMC by increasing its expression. POMC is then cleaved by the prohormone convertase into alpha- melanocyte-stimulating hormone (MSH) and beta-endorphins.
Q. Why are leptin levels high in obese individuals?
A. leptin activity is often high in obese individuals. Leptin and insulin have an intriguing interrelationship. Prenatally, both glucose infusions increase insulin levels and direct infusion of insulin are associated with a rise in leptin. At least in the fetus, leptin may arise from tissues other than fat. Thus, the relatively higher insulin levels in obesity may be a trigger for increased leptin circulation.
Figure 5:
TEACHING CAPTION: Note that AGRP is an antagonist of MC4-R effects and thus activates orexin and MCH in the lateral hypothalamus. Appetite increases. Leptin decreases appetite by decreasing the stimulatory effect of AGRP on these neuropeptides in the lateral hypothalamus. Neuropeptide Y also stimulates orexin and MCH in the lateral hypothalamus, via another pathway, thus increasing appetite. In addition, NPY has an inhibitory effect on the paraventricular nucleus and its neuropeptide Corticotropin Releasing Hormone (CRH) and thyrotropin releasing hormone (TRH) which are involved in increasing energy expenditure via stimulation of the sympathetic nervous system and increasing thyroid function thus resulting in increased thermogenesis. The paraventricular nucleus and its neuropeptides also affect fertility via the pituitary. Inhibition of the paraventricular nucleus by NPY results in decreased fertility.
Figure 6: The impact of Leptin
Leptin --> Leptin Receptors --> POMC --> MSH & beta-endorphins --> MC4-R --> inhibition of Orexin (a peptide that favors energy storage)
TEACHING CAPTION: Note that both mode and activity levels (via beta endorphins) and pigment formation (via MSH) are affected by leptin secretion.
Leptin inhibits the expression of NPY as follows:
1) inhibiting the lateral hypothalamus,
2) decreasing appetite and
3) stimulating paraventricular nuclei (PVN) in the hypothalamus thus increasing energy expenditure and promoting fertility.
Note that Leptin is not the only modulator of NPY.
Thermogenic Effects: CART and links to H-P-Axis
CART increases thermogenesis and energy expenditure while decreasing appetite. CART interacts with leptin, orexin, MCH in the brain, especially the hypothalamus. In this way, CART is an integral player in the hypothalamic-pituitary axis.
Thyroid function and Weight Change
This provides an opportunity to present the work of Ethan Allen Sims in
Vermont. (Students of United States history will be reminded of the attack on British troops at Fort Ticonderoga by Dr. Sims forbearer, General Ethan Allen. It was said to be a turning point in our War for Independence.)
All animal species, humans included, have developed metabolic adaptations to undernutrition whereby changes occur without long-term consequences. (see Blaxter and Waterlow) There are specific metabolic responses to energy restriction that contribute to the difficulty in achieving weight loss among the obese.
Weight stabilizing effects of protein energy malnutrition are mediated by alterations in HPA function. (see EA Sims) Reductions in thyroid hormone (T3 and free T4) below baseline occur with short-term deprivation shifting metabolism from usage to conservation of energy. Metabolic efficiency increases. In 1967, Sims studied Vermont prisoners, none of whome were obese by today's standards. One group was provided caloric intake at 10% below their estimated need. The second was given sufficient energy. The third was given supplements to increase energy intake 10% over estimated need. All were provided sufficient micronutrients, essential ammo acids and fats in the diet or as supplements. The overfed group showed increases in T3, decreases in rT3 associated with accelerated metabolic clearance and production of T3. T4 did not change. Thus thermogenesis increases in states of overnutrition.
More recently, Reinehr and Andler have looked at hormonal responses to weight loss in children.
A FINAL NOTE ON WEIGHT MAINTENANCE
Among the most difficult tasks for a formerly obese person is to maintain weight loss after reducing. As presented elsewhere in the Teacher's Guide (See Part 3, Section 8), a person who formerly weighs 70 kg who reduce to 60 kg will require about 10% less calories to maintain the new body weight of 60 kg as someone who has always weighed 60 kg. Similarly, as Sims et al showed in their classic studies, a person who formerly weighed 50 kg who has been forced to gain to 60kg will require more energy to maintain that 60 kg than the control person who has always weighed 60 kg.
ENDOCRINE SYNDROMES AND OBESITY
Many syndromes occurring in infancy and childhood are associated with obesity. The following table (Table 2) describes these syndromes. A separate module by Bass and Grossman describing Prader Willi syndrome is provided in Part 4 Section X.
Table 2: Endocrine Syndromes
SUMMARY
We have shown that under steady state conditions, obese and lean people have physiological functions that are similar unless there are alterations in pathways such as leptin or leptin receptor deficiency. Outside the steady state, however, obese and lean people are quite different. Loss of body fat triggers multiple appetite stimulating and satiation repressing mechanisms. GI peptides, leptin, CNS pathways and even cellular molecules modulate appetite, metabolism and satiation. How these multiple mechanisms controlling weight go array is evident in obesity syndromes - some of which are outlined in Table 2.
REFERENCES
Arora S, Anubhuti. Role of neuropeptides in appetite regulation and obesity--a review. Neuropeptides. 2006; 40(6); 375-401.
Bacha F. J Clin Endocrinol Metab 2005; 90(5): 2725-30
Blaxter K. (1985) Energy intake and expenditure (in) Blaxter K, Waterlow
JC (eds) Nutritional Adaptation in man. John Libbey. London
Drucker, D.J. The biology of incretin hormones. Cell Metab. 2006. 3; 153-165
Ludwig DS, 2002) The glycemic index: physiological mechanisms relating
to obesity, diabetes, and cardiovascular disease. JAMA. 2002 May
8;287(18)
Mayer J. Regulation of energy intake and body weight: The glucostatic
theory and lipostatic hypothesis. Ann N.Y. Acad of Science. 1955. 65:15-43.
Unger, RH. Hyperleptinemia: protecting the heart from lipid overload. Hypertension, 2005. 46(6): 1031-4.
Verdich C. Int J Obes relat Metab Disord. 2001. 25: 1206-1214.
Lenders C and Hoppin A. Management and Treatment of Obesity. In: Walker W, Watkins J, Duggan C, eds. Nutrition in Pediatrics: Basic Science and Clinical Applications, 3rd edition. B.C. Decker Inc; 2003:chapter 54:917-934.
Rosenbaum M. Obesity in children. In: Caro JF, Ed. Obesity. Endotext.com. Chapter 16. 2002. Available on the internet at www.endotext.org . Accessed November 11, 2005.
Appendix:
Transmethylation or "Lamarck rolling in his grave with glee"
Let's consider the consequence of an OB/OB rat mating with an OB/ob rat with a folate
rich or folate deprived dam.
Our Punet square looks like this:
TABLE 3: Outcome of crossing an OB/OB with an OB/ob rat.
TEACHING CAPTION: One would expect, given sufficient numbers of
matings, that about ˝ of the rats would be classic OB/OB and be fat. The other half would be OB/ob and be lean.
The underlying defect in an OB/OB rat is a failure of leptin secretion. The
pathway within CNS leads to several consequences. One of them is a failure to
produce sufficient melanin. Thus, the OB/OB rat is identifiable at birth because
they are yellowish rather than brown or black.
Q. Can the in-utero environment affect the genetic character of the
offspring?
A. Anyone answering "yes" should turn in his or her medical degree. At east that is what we have all been taught. Jean Baptiste Lamark, a contemporary of Darwin taught that environmental experiences, would affect heredity. Currently considered absurd, in his life time Lamark's view was given equal if not greater respect than that of Darwin.
The answer to our question, however, is "yes." When folate deficient OB/OB rat mother are mated with OB/ob fathers, there is a failure of transmethylation in the formation of the genome for the offspring. Raising mothers to be folate deficient is associated with a distribution of OB/OB to Ob/ob of 60/40. Raising the mothers in an excess of folate changes that ratio to 40/60.
Did I hear singing? That must be Lamark chortling in his grave, "I was
right!"
ANNOTATED ANSWERS
A1. The answer is d. Each of the factors taken alone will result in satiation.
A2. The answer is c. One might expect overweight or obese persons to maintain higher leptin levels than lean persons, but the actual leptin level circulating in humans of all body somatotypes is variable. Overweight individuals with high leptin levels are typically leptin resistant. Adiposity hormones such as leptin and insulin regulate short term food intake to achieve long term energy balance.
A3. The answer is True. Most obese people are in balance with their own homeostatic mechanisms as lean people are. With food deprivation, the natural response mechanisms set in. This occurs in lean children and adults similar to the obese. However, overeating and sedentary lifestyles have resulted in a disruption of energy balance and development of type 2 diabetes.
A4. The answer is True. Semi starvation is indeed the natural state of man.
Given the constant challenges of irregular food supply, the body has developed the ability to maintain energy balance during food deprivation for survival reasons. These include storing fuel during food supply and decrease energy expenditure during food shortage. A formal answer based on pathophysiology is given below.
A5. Multiple GI peptides and peripheral hormones affect the hypothalamus and the central nervous system pathways regulating appetite and energy metabolism. The principle H-P-A axis adaptation is the peripheral conversion of T4 to rT3 rather than T3. This slows energy expenditure until famine passes. In addition, changes in Growth Hormone, ACTH, and prolactin secretion counter satiety mechanisms and stimulate appetite.
