The multiple hormonal factors that influence longitudinal growth—discussed in the previous two subchapters—are themselves responsive to the nutritional intake of a growing individual. For example, amino acids and carbohydrates promote insulin secretion, and amino acids stimulate GH secretion (see pp. 992–994). In addition, the availability of an adequate balanced nutrient supply likely exerts both direct and indirect influences to promote tissue growth. Independent of any hormonal factors, glucose, fatty acids, and amino acids can each influence the transcription of specific genes. Similarly, amino acids can directly activate the signaling pathways involved in regulating messenger RNA (mRNA) translation.
Beyond the effects of macronutrients, the effects of micronutrients can be similarly important in regulating cell growth and, by extension, growth of the organism. An example is iodine, a deficiency of which can produce dwarfism (see p. 1009). In a more global fashion, the effect of nutrient limitation on height can be appreciated by considering the differences in mean height between men in North Korea (165 cm) and South Korea (171 cm). As mentioned on page 990, nutritional deprivation early in life can markedly limit longitudinal growth. Perhaps equally fascinating, and only recently appreciated, is that nutritional deprivation early in life also appears to predispose affected individuals to obesity when they reach middle age. This phenomenon was first noted in epidemiological studies in several European countries that revealed a positive correlation between middle-aged obesity and being born during periods of deprivation during and immediately following the Second World War. Such findings suggest that some level of genetic programming occurs early in life that both diminishes longitudinal growth and predisposes persons to body mass accretion.
The balance between energy intake and expenditure determines body mass
At any age or stage of life the factors that govern body mass accretion relate specifically to the energy balance between intake and expenditure. If energy intake exceeds expenditure over time—positive energy balance (see p. 1173)—body mass will increase, assuming the diet is not deficient in essential macronutrients or micronutrients. Small positive deviations from a perfect energy balance, over time, contribute to the major increase in body weight—the “obesity epidemic”—that affects many middle-aged adults, and increasingly adolescents, in developed societies. For example, if energy intake in the form of feeding exceeds energy expenditure by only 20 kcal (1 tsp of sugar) daily, over 1 year a person would gain ~1 kg of fat, and over 2 decades, ~20 kg.
Indeed, it is remarkable that many adults maintain a consistent body weight for decades essentially in the absence of conscious effort. Thus, a finely tuned regulatory system must in some manner “monitor” one or more aspects of body mass, direct the complex process of feeding (appetite and satiety) to replete perceived deficiencies, and yet avoid excesses.
Energy expenditure comprises resting metabolic rate, activity-related energy expenditure, and diet-induced thermogenesis
We can group energy expenditure into three components:
1. Resting metabolic rate (RMR). The metabolism of an individual who is doing essentially nothing (e.g., sleeping) is known as the RMR (see p. 1170), which amounts to ~2100 kcal/day for a young 70-kg adult. The RMR supports maintenance of body temperature, the basal functioning of multiple body systems (e.g., heartbeat, GI motility, ventilation), and basic cellular processes (e.g., synthesizing and degrading proteins, maintaining ion gradients, metabolizing nutrients).
2. Activity-related energy expenditure. As we wake up in the morning and begin to move about, we expend more energy than resting metabolism. Exercise or physical work can have a major impact on total daily energy expenditure and varies widely across individuals, and within an individual on a day-to-day basis. We also expend energy in activities not classically regarded as exercise or heavy work, such as tapping the foot while sitting in a chair, looking about the room during a physiology lecture, typing at a keyboard—activities dubbed non–exercise-associated thermogenesis or NEAT. Such energy expenditures can vary 3- to 10-fold across individuals and can account for 500 kcal or more of daily energy expenditure. NEAT differences, over time, could contribute considerably to differences in weight gain by individuals with identical caloric intake.
3. Diet-induced thermogenesis. Eating requires an additional component of energy expenditure for digesting, absorbing, and storing food. Typically, diet-induced thermogenesis accounts for 10% of daily energy expenditure. Proteins have a higher thermic effect than either carbohydrates or fats (i.e., the metabolism and storage of proteins requires more energy).
Each of these three components of energy expenditure can vary considerably from day to day and is subject to regulation. For example, thyroid hormone is a major regulator of thermogenesis (see p. 1013). Overproduction of thyroid hormone increases both RMR and NEAT, whereas thyroid hormone deficiency has the opposite effect. N48-3
Effect of Hyperthyroidism on Basal Metabolic Rate
Contributed by Emile Boulpaep, Walter Boron
One of the earliest tests for hyperthyroidism was to measure basal metabolic rate (BMR), as discussed in the text on page 1170. This method is not used today because BMR can be affected by other factors (e.g., body size, fever, catecholamines, fasting), so changes cannot be related specifically to the thyroid. In addition, it is cumbersome to measure BMR accurately compared with obtaining serum estimates of thyroid hormone concentrations or activity.
Nevertheless, all things being equal, thyroid hormone increases the BMR. The difference between BMR and RMR is discussed on page 1170.
Hypothalamic centers control the sensations of satiety and hunger
Classic studies in which investigators made lesions in, or electrically stimulated, specific brain regions identified two areas in the hypothalamus that are important for controlling eating. A satiety center is located in the ventromedial nucleus (VMN; see Fig. 47-3). Electrical stimulation of the satiety center elicits sensations of satiety, even when an animal is in the presence of food. Conversely, a lesion of the satiety center causes continuous food intake (hyperphagia) even in the absence of need. A hunger (or feeding) center is located in the lateral hypothalamic area (see Fig. 47-3). Electrical stimulation of this center elicits a voracious appetite, even after an animal has ingested adequate amounts of food. A lesion of the hunger center causes complete and lasting cessation of food intake (aphagia).
Leptin tells the brain how much fat is stored
Only in the last 2 decades have we begun to understand regulatory mechanisms that maintain body mass, an advance made possible by the study of mouse models of obesity. One monogenic model is the Ob/Ob strain of hyperphagic mice that develop morbid obesity; affected mice typically weigh >100% more than unaffected animals of the same strain. In parabiosis experiments in which an Ob/Ob mouse was surgically connected to a wild-type mouse (Fig. 48-8A), the Ob/Ob mouse lost weight, which suggests that such mice lack a blood-borne factor. Another model of monogenic obesity is the (Db/Db) mouse, named Db because it secondarily develops type 2 diabetes (see Box 51-5). Like Ob/Ob mice, Db/Db mice are hyperphagic, with adult body weights ~100% greater than those of lean littermates. However, in parabiosis experiments connecting a Db/Db and a wild-type mouse (see Fig. 48-8B), the wild-type mouse starved. Finally, in parabiosis experiment connecting an Ob/Ob to a Db/Db mouse (see Fig. 48-8C), the Ob mouse lost weight but the Db mouse remained obese. These results indicate the following:
1. The Db mouse makes an excess of the blood-borne factor that cures the Ob mouse.
2. The Db mouse lacks the receptor for this factor.
3. Absence of the receptor in the Db mouse removes the negative feedback, which leads to high levels of the blood-borne factor.
FIGURE 48-8 Parabiosis experiments. In parabiotically coupled mice, ~1% of the cardiac output of one mouse goes to the other, and vice versa, so that the animals exchange blood-borne factors. Wt, wild type.
In 1994, Jeffrey Friedman and his colleagues used positional cloning to identify leptin (from the Greek leptos [thin]), the blood-borne factor lacked by Ob mice. Leptin is a 17-kDa protein made almost exclusively in adipocytes. The replacement of leptin in Ob/Ob mice leads to rapid weight loss. In 1995, Tepper and collaborators cloned the leptin receptor (LEP-R). The deficiency of this receptor in Db mice makes them leptin resistant. LEP-R is a tyrosine kinase–associated receptor (see Fig. 3-12D) that signals through JAK2 and STAT (see Fig. 4-14). Among the several splice variants of LEP-R, the “long-form” is richly expressed in the arcuate nucleus of the hypothalamus and several other CNS sites.
Although leptin acts on numerous tissues, it somehow crosses the blood-brain barrier (see pp. 284–287) and modulates neurons in the arcuate nucleus of the hypothalamus that secrete pro-opiomelanocortin (see Fig. 50-4) and influence feeding behavior. These same neurons also have insulin receptors. Plasma leptin levels in humans appear to rise in proportion to the mass of adipose tissue (Box 48-3). Conversely, the absence of leptin produces extreme hyperphagia, as in Ob/Ob mice. Plasma leptin has a half-time of ~75 minutes, and acute changes in food intake or fasting do not appreciably affect leptin levels. In contrast, insulin concentrations change dramatically throughout the day in response to dietary intake. Thus, it appears that leptin in some fashion acts as an intermediate- to long-term regulator of CNS feeding behavior, whereas insulin (in addition to intestinal hormones like glucagon-like peptide 1 [GLP-1] and cholecystokinin [CCK]) is a short-term regulator of the activity of hypothalamic feeding centers.
One approach for gauging the extent to which human body mass is appropriate for body height is to compute the body mass index (BMI):
BMIs fall into four major categories: N48-4
1. Underweight: <18.5
2. Normal weight: 18.5 to 24.9
3. Overweight: 25 to 29.9
4. Obesity: ≥30
A caution in using BMI is that it takes no account of an excess or deficiency in body water content, and thus its use is inappropriate in edematous states like cirrhosis or heart failure. Although a BMI of ≥30 is an indication of obesity, BMI is not a direct measure of adipose-tissue fat mass (see p. 1243). Obesity is an area of intense investigation driven in part by the obesity epidemic that is adversely affecting the health of a large fraction of the human population.
The demonstration that replacement of leptin in Ob/Ob mice led to rapid weight loss raised considerable enthusiasm for the potential of leptin as a pharmacological agent in the treatment of human obesity. Indeed, extremely rare individuals have been identified with autosomal recessive monogenic obesity secondary to leptin deficiency, like the Ob/Ob mouse. As expected, these individuals respond to exogenous leptin administration with a marked reduction in body weight. However, investigators soon appreciated that the vast majority of obese humans are not leptin deficient. Quite the contrary, plasma leptin concentrations increase proportionately to BMI, which is a rough estimate of adipose-tissue fat mass.
Although obese people generally are not leptin deficient, approximately one third of the obese lose weight in response to exogenous leptin. These individuals are leptin resistant, but they eventually respond to sufficiently high levels of the hormone. In the other two thirds of obese people, the leptin resistance is so severe that they fail to respond to the exogenous hormone. Lean people lose weight in response to leptin. Persons with congenital lipodystrophy lack adipocytes and thus are leptin deficient. Affected individuals are lean but have excess triacylglycerols in muscle and liver, are very insulin resistant, and develop diabetes. Treatment with leptin corrects this metabolic disorder.
Other mutations besides those of the leptin gene cause monogenic human obesity. Extremely rare are mutations of the leptin receptor gene (analogous to the defect in the Db mouse) and mutations of the POMC gene (leading to loss of the anorexigenic α-MSH). A more common cause of monogenic human obesity is a mutation in the melanocortin receptor MC4R, the target of α-MSH.
Currently no satisfactory pharmacological approaches are available to treat obesity. Given the prevalence of obesity and the likelihood that any pharmacological intervention would need to be long-term, antiobesity drugs are of significant interest within the pharmaceutical industry. Among the agents in late stages of clinical testing, none directly targets the hypothalamic pathways described here. However, because feeding is such a complex behavior—being influenced by hunger, reward and pleasure centers in the CNS, as well as peripheral signals (e.g., gastric distention)—agents may be effective even if they only secondarily affect the hypothalamic control system.
Body Mass Index
Contributed by Emile Boulpaep, Walter Boron
To see how to compute BMI, visit http://nhlbi/support.com/bmi/. However, the simplistic formula for computing BMI can be misleading in some cases. For example, in the cachexia of cancer, the patient loses not only adipose tissue, but also fat-free mass. Thus, the fall in the BMI is greater than the fall in adipose mass. On the other hand, the accumulation of extracellular fluid in a patient with ascites (see Box 24-2) or interstitial edema (see Box 20-1) does not reflect an increase in adipose tissue. Thus, the rise in BMI can be greater than any rise in the mass of adipose tissue.
In addition to acting to control appetite, leptin promotes fuel utilization. Indeed, leptin-deficient humans paradoxically exhibit some characteristics of starvation (e.g., fuel conservation via decreased thermogenesis and basal metabolic rate).
Leptin and insulin are anorexigenic (i.e., satiety) signals for the hypothalamus
At least two classes of neurons within the arcuate nucleus contain receptors for leptin and insulin. These neurons, in turn, express neuropeptides. One class of neurons produces pro-opiomelanocortin (POMC), whereas the other produces neuropeptide Y (NPY) and agouti-related protein (AgRP).
Insulin and leptin each stimulate largely distinct subgroups of POMC-secreting neurons (Fig. 48-9), which produce POMC. At their synapses, POMC neurons release a POMC cleavage product, the melanocortin α-melanocyte–stimulating hormone (α-MSH; see Fig. 50-4), which in turn binds to MC3R and MC4R melanocortin receptors on second-order neurons. Stimulation of these receptors not only promotes satiety and decreases food intake—that is, α-MSH is anorexigenic (from the Greek a [no] + orexis [appetite])—but also increases energy expenditure via activation of descending sympathetic pathways. An indication of the importance of this pathway is that ~4% of individuals with severe, early-onset obesity have mutations in MC3R or MC4R. POMC neurons also synthesize another protein—cocaine- and amphetamine-regulated transcript (CART)—which, like α-MSH, is anorexigenic.
FIGURE 48-9 Control of appetite. ARC, arcuate nucleus; CART, cocaine- and amphetamine-regulated transcript; DMN, dorsomedial hypothalamic nucleus; LHA, lateral hypothalamic area; NTS, nucleus tractus solitarii; PVN, paraventricular nucleus; VMN, ventromedial hypothalamic nucleus.
In addition to stimulating POMC neurons, both insulin and leptin can also suppress neurons in the arcuate nucleus that release NPY and AgRP at their synapses (see Fig. 48-9). NPY activates NPY receptors (which are GPCRs)—predominantly Y1R and Y5R—on secondary neurons, thereby stimulating eating behavior. AgRP binds to and inhibits MC4R melanocortin receptors on the secondary neurons in the POMC pathway, thereby inhibiting the anorexigenic effect of α-MSH. Thus, both NPY and AgRP are orexigenic. The yellow obese or agouti mouse overexpresses the agouti protein, which inhibits melanocortin receptors. Overinhibition of MC1R on melanocytes inhibits the dispersion of pigment granules (leading to yellow rather than dark fur). Overinhibition of MC3R and MC4R on anorexigenic neurons blocks the action of α-MSH (leading to obesity).
The POMC/CART and NPY/AgRP neurons project to secondary neurons in five major locations (see Fig. 48-9; see also Fig. 47-3):
1. Lateral hypothalamic area (LHA). In this hunger center (see p. 1001), NPY/AgRP neurons stimulate—but POMC neurons inhibit—secondary neurons. These project throughout the brain and release the orexigenic peptides melanin-concentrating hormone (MCH) or orexins A and B.
2. Ventromedial hypothalamic nucleus (VMN). This nucleus is a satiety center (see p. 1001).
3. Dorsomedial hypothalamic nucleus (DMN).
4. Paraventricular nucleus (PVN). This nucleus contains neurons that in turn project to both cerebral cortex and areas of the brainstem (see Fig. 47-3).
5. Nucleus tractus solitarii (NTS). This nucleus (see p. 348) integrates sensory information from the viscera and also receives input from paraventricular neurons.
Ghrelin is an orexigenic signal for the hypothalamus
Signals originating from the periphery can be not only anorexigenic (i.e., promoting satiety)—as in the case of leptin (from adipose tissue) and insulin (from the pancreas)—but also orexigenic (i.e., promoting appetite). One of these is ghrelin (see pp. 992–993), made in response to fasting by specialized endocrine cells in the gastric mucosa. Indeed, systemically administered ghrelin acutely increases food intake when it is given at physiological doses in both animals and humans. Circulating ghrelin concentrations, however, appear to be lower in obese than in lean humans, which suggests that ghrelin does not drive the increased caloric intake in the obese. However, gastric bypass procedures in morbidly obese patients cause a dramatic decline in ghrelin levels, along with a decline in body weight and food consumption.
As discussed previously, ghrelin binds to GHSR1a (see p. 993), which is present in neurons of the arcuate nucleus as well as vagal afferents. Some hypothalamic neurons themselves contain ghrelin, and injection of ghrelin into the cerebral ventricles stimulates feeding. It is not clear to what extent circulating ghrelin promotes appetite via vagal afferents versus hypothalamic receptors. As noted above, ghrelin also promotes the secretion of GH and thus appears to have a role in both longitudinal growth and body mass accretion.
Plasma nutrient levels and enteric hormones are short-term factors that regulate feeding
Investigators have proposed various theories to explain the short-term regulation of food intake, including models focusing on the regulation of levels of blood glucose (glucostatic), amino acids (aminostatic) or lipids (lipostatic). For example, hypoglycemia produces hunger and also increases the firing rate of glucose-sensitive neurons in the hunger center in the LHA, but decreases the firing rate of glucose-sensitive neurons in the satiety center in the VMN. Hypoglycemia also activates orexin-containing neurons in the LHA.
Feedback from the GI tract also controls the short-term desire for food (see Fig. 48-9). GI distention triggers vagal afferents that, via the NTS (see p. 348), suppress the hunger center. Peripherally administering any of several GI peptide hormones normally released in response to a meal—gastrin-releasing peptide (GRP; see p. 868), CCK (see pp. 882–883), peptide YY (PYY; see p. 892), SS (see pp. 993–994), glucagon (see pp. 1050–1053), GLP-1 (see p. 1041)—reduces meal size (i.e., these substances are anorexigenic). The most important is CCK, which is more effective when injected directly into the peritoneal cavity; this effect requires an intact vagus nerve. Therefore, CCK—like gastric distention—may act via vagal afferents. Additionally, an oropharyngeal reflex responds to chewing and swallowing; it may meter food intake, thus inhibiting further eating after a threshold.
An important aspect of our increasing understanding of the neuroendocrine control systems that regulate appetite, satiety, and energy expenditure and thereby body mass is the further affirmation that these processes have a genetic and biochemical basis. Two other factors that influence body mass are cortical control (e.g., “willpower”) and environment (e.g., the availability of high-calorie foods). Our emerging appreciation of the biological basis of obesity may allow a more scientific and clinical approach to therapeutic interventions—rather than simply blaming affected patients for their obesity.