Clinical Chemistry 50:9

1511–1525 (2004) Review

Endocrine Regulation of Energy Metabolism:

Background: Recent studies point to the adipose tissue Summary: The functional roles, structures, synthesis,
as a highly active endocrine organ secreting a range of analytical aspects, and clinical significance of leptin,
hormones. Leptin, ghrelin, adiponectin, and resistin are ghrelin, adiponectin, and resistin are summarized.
considered to take part in the regulation of energy © 2004 American Association for Clinical Chemistry
metabolism.
Approach: This review summarizes recent knowledge Leptin
on leptin and its receptor and on ghrelin, adiponectin, structure and synthesis
and resistin, and emphasizes their roles in pathobio- Leptin, the product of the ob gene, is a recently discovered
chemistry and clinical chemistry. single-chain proteohormone with a molecular mass of 16
Content: Leptin, adiponectin, and resistin are produced kDa that is thought to play a key role in the regulation of
by the adipose tissue. The protein leptin, a satiety body weight (1 ). Its amino acid sequence exhibits no
hormone, regulates appetite and energy balance of the major homologies to other proteins (2 ). This product of
body. Adiponectin could suppress the development of the ob gene (obesity mice) is named leptin from the Greek
atherosclerosis and liver fibrosis and might play a role word “leptos”, meaning thin. Leptin is produced by
as an antiinflammatory hormone. Increased resistin con- differentiated adipocytes, although production has been
centrations might cause insulin resistance and thus demonstrated in other tissues, such as the fundus of the
could link obesity with type II diabetes. Ghrelin is stomach, the skeletal muscle, the liver, and the placenta
produced in the stomach. In addition to its role in (3 ). Leptin acts on the central nervous system, in partic-
long-term regulation of energy metabolism, it is in- ular the hypothalamus, suppressing food intake and
volved in the short-term regulation of feeding. These stimulating energy expenditure (4 ).
hormones have important roles in energy homeostasis, Leptin receptors belong to the cytokine class I receptor
glucose and lipid metabolism, reproduction, cardiovas- family (5 ) and are found ubiquitously in the body (6 ),
cular function, and immunity. They directly influence indicating a general role of leptin that is currently not
other organ systems, including the brain, liver, and fully understood. A circulating form of the leptin receptor
skeletal muscle, and are significantly regulated by nu- exists, which acts as one of several leptin-binding proteins
(7 ). Abnormalities in db/db mice (diabetic mice) include
tritional status. This newly discovered secretory func-
severe leptin resistance caused by leptin receptor muta-
tion has extended the biological relevance of adipose
tion.
tissue, which is no longer considered as only an energy
Several alternatively spliced isoforms of the leptin
storage site.
receptor have been identified (Ob-Ra, Ob-Rb, Ob-Rc,
Ob-Rd, and Ob-Re) (8 ). Ob-Ra is thought to be a leptin
transporter, and Ob-Re is the soluble form of the trans-
Institute of Clinical Chemistry and Pathobiochemistry and Central Labo-
membrane leptin receptor. Ob-Rb is a long form contain-
ratory, Rhenish-Westphalian Technical University (RWTH)-University Hospi- ing an intracellular signaling domain and shows high
tal Aachen, Pauwelsstrasse 30, D-52074 Aachen, Germany. peak concentrations in the feeding centers of the hypo-
*Author for correspondence. Fax 49-241-8082512; e-mail umeier@ukaachen.
thalamus (9 ), consistent with leptin being the afferent
de.
Received February 10, 2004; accepted June 28, 2004. signal informing the central nervous system of the body
Previously published online at DOI: 10.1373/clinchem.2004.032482 fat status. This concept is further supported by the obser-

1511
1512 Meier and Gressner: Endocrine Regulation of Energy

Fig. 1. Action of leptin on the hypothalamus and peripheral organs (pancreas, liver. and skeletal muscle).
IL-1, interleukin-1; T3, triiodothyronine; T4, thyroxin.

vation that leptin-deficient (ob/ob) mice and humans can concentrations in response to food deprivation are re-
be successfully treated with leptin. Leptin was therefore sponsible for the starvation-induced suppression of the
initially considered for treatment of obesity. hypothalamic-pituitary-gonadal axes (14 ) as well as the
Obese individuals, however, often have increased lep- malfunction of several other neuroendocrine axes. Thus it
tin concentrations (10 ), and leptin administration shows seems that leptin may act as the critical link between
only very limited effects (11 ). Recent data have indicated adipose tissue, hypothalamic centers regulating energy
that this is likely the result of desensitization for the leptin homeostasis, and the reproductive system, indicating
signal, a phenomenon now often referred to as leptin whether adequate energy reserves are present for normal
resistance. This may occur on at least two distinct levels: reproductive function (15 ).
saturable transport of leptin across the blood– brain bar- These actions may, at least in part, be explained by the
rier and abnormalities in the extent of leptin receptor suppressive effect of leptin on neuropeptide Y (NPY)1
activation and/or signal transduction (12 ). In addition to production and secretion by neurons in the arcuate nu-
its role via the central nervous system, leptin also has cleus (16 ). NPY is a strong stimulator of appetite (17 ) and
direct effects on a series of peripheral tissues, implying a is known to be involved in the regulation of various
much more complex leptin axis than was originally hy- pituitary hormones: suppression of growth hormone
pothesized (13 ).

functions
1
In addition to its metabolic effects, leptin has been shown Nonstandard abbreviations: NPY, neuropeptide Y; GH, growth hormone;
BMI, body mass index; TNF, tumor necrosis factor; GHS-R, growth hormone
to have a strong influence on several endocrine axes (Fig.
secretagogue receptor; AGRP, agouti-related peptide; IGF, insulin-like growth
1). factor; PPAR, peroxisome proliferator-activated receptor; FIZZ, found in
It was shown recently in humans that decreasing leptin inflammatory zone; and RELM, resistin-like molecule.
 Clinical Chemistry 50, No. 9, 2004 1513

(GH) through stimulation of somatostatin (18 ), suppres- reduces hepatic fat mass and improves insulin sensitivity
sion of gonadotropins (19 ), or stimulation of the pitu- in humans suffering from this condition (29 ). Suppression
itary–adrenal axis (20 ). of the fatty-acid-synthesizing enzyme stearyl-CoA de-
Orexins (orexin-A and -B; also known as hypocretin-1 saturase-1 can correct the hypometabolic phenotype of
and -2) were recently discovered in the hypothalamus. leptin deficiency, implying that leptin not only works via
Orexins were initially thought to function in the hypotha- central anorectic effects but also by increasing hepatic
lamic regulation of feeding behavior, but orexin-contain- fatty acid oxygenation (30 ). The main functions of leptin
ing fibers and their receptors are also distributed in parts and the other hormones of the energy metabolism are
of the brain closely associated with the regulation of summarized in Table 1.
cardiovascular and autonomic functions. Functional stud-
ies have shown that these peptides are involved in car- Soluble leptin receptor. The long isoform of the leptin
diovascular and sympathetic regulation (21 ). Although receptor, or Ob-Rb, consists of 1162 amino acids and is the
the pathophysiologic role of the sympathoexcitatory ef- only isoform with clearly demonstrated signaling capabil-
fects of leptin and orexins is not yet clear, the close ity. Circulating leptin crosses the blood– brain barrier and
relationship between obesity, hypertension, and altered binds to its receptor in the hypothalamus where it acti-
cardiovascular responses has been documented (22 ). Lep- vates the JAK-STAT3 pathway (31 ). Neuronal-specific
tin and orexins may therefore be the chemical mediators ablation of Ob-Rb leads to obesity, clearly indicating that
in the brain responsible for the generation and mainte- the weight-reducing properties of leptin are exerted cen-
nance of hypertension, which is associated with condi- trally (32 ).
tions of energy imbalance, such as obesity. High concentrations of the short isoforms Ob-Ra and
The most important variable that determines circulat- Ob-Rc can be found in choroid plexus and brain microves-
ing leptin concentrations is body fat mass (23 ). Obviously, sels (33 ), suggesting their role in blood– brain barrier
under conditions of regular eating cycles, leptin reflects transport. This idea is further supported by observations
the proportion of adipose tissue (24 ), showing an expo- in mouse models for obesity (34 ) and by the use of an in
nential relationship. This constitutive synthesis of leptin is vitro leptin transport assay (35 ). The secreted isoform can
modulated by several nonhormonal and hormonal vari- be generated either by alternative splicing (Ob-Re) or by
ables. Stimulators in both rodents and humans are over- ectodomain shedding and may be involved in modulating
feeding, insulin, and glucocorticoids (25 ). Suppression leptin activity (36 ). Because the soluble leptin receptor
has been shown for fasting (26 ), cAMP, and ␤3-adrenore- affects the effect of leptin on food intake and body weight
ceptor agonists (27 ). It has been demonstrated that leptin in ob/ob mice, regulated ectodomain shedding of mem-
production occurs after increases in insulin in response to brane-spanning leptin receptors may represent a novel
feeding, and a decrease in leptin concentrations follows mechanism for regulating the biological activity of leptin
decreases in insulin during fasting. Early studies reported (37 ).
no acute effect of eating on leptin concentrations, but later
studies demonstrated that meals and insulin acutely affect analytical aspects
leptin concentrations (28 ). For clinical purposes, it is important to note that serum
Patients with lipodystrophy have significantly reduced leptin concentrations show a moderate circadian variation
plasma leptin concentrations. The administration of leptin with a peak during the night at ⬃0200 (38 ). The leptin

Table 1. Molecular properties, synthesis, and main functions of leptin and the other hormones of the energy metabolism.
Molecular Location of main
Molecule mass, kDa synthesis Function
Leptin 16 Adipose tissue ● Conveys information to the hypothalamus on the amount of energy stored in fat
● Suppresses appetite
● Affects energy expenditure
Soluble leptin 90 Blood ● Soluble form of the transmembrane leptin receptor
receptor ● Leptin-binding protein that transports leptin to the blood–brain barrier
in the hypothalamus
Ghrelin 3.3 Stomach ● Conveys information to the hypothalamus and stimulates appetite,
enhances use of carbohydrates and reduces fat utilization, increases
gastric motility and acid secretion
Adiponectin 30 Adipose tissue ● Decreases insulin resistance
● Decreases blood glucose concentrations
Resistin 12.5 Adipose tissue ● In rodents, causes tissues to become less sensitive to insulin
(increases insulin resistance)
● Actions in humans not established
1514 Meier and Gressner: Endocrine Regulation of Energy

concentrations at this time are ⬃30 –100% higher than the nervosa increased after partial refeeding. Other studies
concentrations measured in the morning or early after- showed that opposite modifications occur in circulating
noon. This variation, together with the influence of food concentrations of leptin and soluble leptin receptor across
intake, needs to be taken into account when blood sam- the eating-disorder spectrum (anorexia nervosa, bulimia
ples are collected. Under fairly standardized conditions, nervosa, and binge-eating disorder) (41 ).
i.e., normal eating cycles and blood sampling in the For the appropriate interpretation of leptin concentra-
morning or early afternoon, a single leptin measurement tions, reference intervals are required. Because body fat
is informative. mass is the major confounding variable, these ranges
Leptin in serum is stable for at least five freeze–thaw should be referred to measures of the percentage body fat
cycles. There is no alteration in measured leptin concen- such as BMI (42 ). Leptin concentrations are higher in
trations in samples stored at ⫺20 °C over a 2-year period. females than in males, and an age dependence was shown
Samples are stable for at least 2 months when stored at in children and adolescents (43 ). Reference intervals re-
4 °C (8 ). The stability properties of leptin and the other ferring to measures of body fat should therefore be
hormones (39 ) of energy metabolism are summarized in stratified according to gender and pubertal development.
Table 2. Developmental changes in circulating concentrations
Some manufacturers have developed a sensitive RIA of the soluble leptin receptor and leptin have been shown
suitable for the measurement of leptin in fluids such as in humans (10 ). In both sexes, the increase in leptin
cerebrospinal fluid or in serum from patients with an- concentration with age was associated with a decrease in
orexia nervosa, which have much lower leptin concentra- the concentration of soluble leptin receptor, and age-
tions (40 ). ELISA procedures are now also commercially related changes in the concentrations of both leptin and its
available: serum concentrations of leptin and soluble soluble receptor preceded the pubertal increase in go-
leptin receptor in female patients with anorexia nervosa nadal hormones. Leptin concentrations ⬎10 ␮g/L were a
were evaluated by use of commercially available ELISAs. strong predictor of soluble leptin receptor concentrations,
For the measurement of leptin, there was a good correla- but this predictive value decreased as leptin concentra-
tion (r ⫽ 0.95) between the sensitive RIA from Mediagnost tions decreased. In young individuals, there were no
(lower limit of detection, 0.04 ␮g/L; linear range, 0 –16 gender differences in serum leptin, but boys had higher
␮g/L; intraassay CV ⬍5%; interassay CV ⫽ 7.6%) and the soluble leptin receptor concentrations. In adults, neither
ELISA from Biovendor (lower limit of detection, 0.5 ␮g/L; leptin nor soluble leptin receptor changed with age, but
linear range, 1–50 ␮g/L; intraassay CV ⫽ 3%; interassay serum leptin was higher and soluble leptin receptor was
CV ⫽ 7%). lower in women than men. In women, there is a signifi-
Soluble leptin receptor concentrations in human serum cant negative correlation between soluble leptin receptor
are measurable with a sandwich ELISA from Biovendor and leptin.
(lower limit of detection, 0.4 kilounits/L; linear range,
2–100 kilounits/L; intraassay CV ⫽ 3%; interassay CV ⫽ clinical significance of leptin and its soluble
3.5%; 2 ng of the recombinant calibrators are equivalent to receptor
1 unit). Soluble leptin receptor concentrations in patients Hyperleptinemia is an essential feature of human obesity.
with anorexia nervosa were higher than in healthy indi- The BMI is the best predictor of circulating leptin concen-
viduals and were not affected by partial refeeding. In trations. Although the ob gene is differentially expressed
contrast, body mass index (BMI), body fat content, and in different fat compartments, apart from total body fat,
serum leptin concentrations in patients with anorexia upper or lower body adiposity and visceral fat do not
influence basal leptin concentrations. Similarly, age, basal
glucose concentrations, and ethnicity do not influence
Table 2. Stability properties of leptin and its receptor,
circulating leptin concentrations. Only in insulin-sensitive
ghrelin, adiponectin, and resistin.
individuals do basal concentrations of insulin and leptin
Molecule Stability
correlate positively even after factoring in body fat. Dia-
Leptin ● Stable over five freeze–thaw cycles
betes does not influence leptin secretion in both lean and
● Stable at ⫺20 °C over 2 years
obese individuals. In the eating disorders anorexia ner-
● Stable at 4 °C for 2 months
vosa and bulimia nervosa, leptin concentrations are not
Soluble leptin ● Stable over repeated freeze–thaw cycles up-regulated but simply reflect BMI and, probably, body
receptor
fat (44 ). In spite of a strong correlation between body fat
Active ghrelin ● Very unstable and labile in serum because and leptin concentrations, there is great heterogeneity in
of the nature of the octanoyl group on serine-3
● Samples and assay reagents should be
leptin concentrations at any given index of body fat.
kept on ice Approximately 5% of obese populations can be regarded
Adiponectin ● Possibility of long-term storage at ⫺20 °C
as “relatively” leptin deficient and could benefit from
● Stable over repeated freeze/thaw cycles
leptin therapy.
Leptin has dual regulation in human physiology. Dur-
Resistin ● Stable over repeated freeze/thaw cycles
ing periods of weight maintenance, when energy intake
 Clinical Chemistry 50, No. 9, 2004 1515

and energy output are equal, leptin concentrations reflect olism. Dietary fat and fructose, which do not increase
total body fat mass. However, in conditions of negative insulin secretion, lead to reduced leptin production, sug-
(weight-loss programs) and positive (weight-gain pro- gesting a mechanism for high-fat/high-sugar diets to
grams) energy balances, the changes in leptin concentra- increase energy intake and weight gain (49 ).
tions function as a sensor of energy imbalance. This latter Because leptin has also been shown to be of great
phenomenon is best illustrated by short-term fasting and importance for reproductive functions, possible new
overfeeding experiments. Within 24 h of fasting, leptin pathophysiologic mechanisms may be discovered relating
concentrations decrease to ⬃30% of initial basal values. infertility to insufficient leptin production (48 ).
Massive overfeeding over a 12-h period increases leptin Insulin resistance and abdominal obesity are associated
concentrations by ⬃50% of initial basal values. Meal with low soluble leptin receptor concentrations and a low
ingestion does not acutely regulate serum leptin concen- ratio of bound to free leptin independent of fat mass. Low
trations. A few studies have shown a modest increase in soluble receptor concentrations and low bound/free lep-
leptin secretion at supraphysiologic insulin concentra- tin ratios segregate with components of the metabolic
tions 4 – 6 h after insulin infusion (45, 46 ). Similar to other syndrome. Low soluble receptor concentrations and a low
hormones, leptin secretion shows circadian rhythm and fraction of specifically bound leptin are markers of leptin
oscillatory pattern. The nocturnal increase of leptin secre- resistance, which is independently associated with insulin
tion is entrained by mealtime, probably as a result of the resistance and abdominal obesity and may constitute an
cumulative hyperinsulinemia that occurs over the entire additional component of the metabolic syndrome (50 ).
day. Patients with advanced chronic heart failure have
Like other growth factors and cytokines, leptin-binding increased serum concentrations of leptin and its soluble
proteins, including soluble leptin receptor, are present in receptor. Leptin may participate in the catabolic state
human serum. In lean individuals, the majority of leptin leading to the development of cardiac cachexia in the
circulates in the bound form, whereas in obese individu- course of chronic heart failure (51 ).
als, the majority of leptin is present in the free form. When In patients with chronic hepatitis C and higher BMI
free-leptin concentrations are compared between lean and and blood glucose concentrations, the severity of liver
obese individuals, even more pronounced hyperleptine- fibrosis is associated with serum leptin. Tumor necrosis
mia in obesity is observed than that reported by measur- factor-␣ (TNF-␣) is a putative candidate involved in the
ing total leptin concentrations. During short-term fasting, mechanism (52 ). Increasing concentrations of leptin are
free-leptin concentrations in lean individuals decrease in detected in fibrotic and cirrhotic livers, whereas concen-
much greater proportion than those in obese individuals. trations of the receptor protein remained unchanged (53 ).
In lean individuals with a relatively small energy store
and particularly during food deprivation, leptin circulat- Ghrelin
ing predominantly in the bound form could be the mech- Ghrelin was discovered as the peptide hormone that
anism that restricts its availability to hypothalamic leptin potently stimulates release of GH from the anterior pitu-
receptors to produce the inhibiting effect of leptin on itary. It was subsequently determined that ghrelin, along
food intake and/or energy metabolism. Unlike marked with several other hormones, has significant effects on
changes in serum leptin, leptin in cerebrospinal fluid is appetite and energy balance.
only modestly increased in obese individuals, and the
ratio of leptin in the cerebrospinal fluid to that in serum structure
decreases logarithmically with increasing BMI. If leptin Ghrelin is synthesized as a preprohormone, which is
concentrations in the cerebrospinal fluid are any indica- proteolytically processed to a 28-amino acid peptide (3.3
tion of brain interstitial fluid concentrations, then hypo- kDa). A postsynthetic modification takes place in which
thalami of obese individuals are not exposed to abnor- an n-octanoic acid residue is bound to one of the amino
mally increased leptin concentrations (47 ). acids; this modification is necessary for biological activity
In a small percentage of patients, however, leptin (54 ). Synthesis occurs predominantly in epithelial cells
concentrations have been found to be inappropriately low lining the fundus of the stomach; only small amounts are
with respect to fat mass. It remains for future studies to produced in the placenta, kidney, pituitary, and hypothal-
confirm that these patients represent a new pathophysio- amus.
logic entity: leptin deficiency (48 ). In addition to the The ghrelin receptor was known well before ghrelin
well-known consequences of absolute leptin deficiency, was discovered. Cells within the anterior pituitary have a
individuals with heterozygous leptin gene mutations receptor that, when activated, potently stimulates secre-
have low circulating concentrations of leptin and in- tion of GH; that receptor was named the growth hormone
creased body adiposity. Leptin treatment dramatically secretagogue receptor (GHS-R). The natural ligand for the
improves metabolic abnormalities (insulin resistance and GHS-R was announced in 1999 as ghrelin and was named
hyperlipidemia) in patients with relative leptin deficiency for its ability to provoke GH secretion (the suffix “ghre”
attributable to lipoatrophy. Leptin production is primarily means grow) (55 ).
regulated by insulin-induced changes of adipocyte metab- Ghrelin receptors are present on the cells in the pitu-
1516 Meier and Gressner: Endocrine Regulation of Energy

itary that secrete GH and have also been identified in the in rodents as well as in humans (63 ) and is strongly
hypothalamus, heart, and adipose tissue (56 ). involved in the regulation of energy homeostasis (64 ).
Although several other potent orexigenic peptides, in-
functions cluding NPY, AGRP, and melanin-concentrating hor-
The discovery of ghrelin contributed considerably to the mone, have previously been characterized in the brain,
understanding of the regulation of GH secretion (Fig. 2). ghrelin is the first food-intake-stimulating signal originat-
Ghrelin activates GHS-Rs located on the pituitary and ing from the stomach.
GH-releasing hormone-containing neurons in the hypo- In adult humans, plasma ghrelin concentrations in-
thalamic arcuate nucleus, stimulating GH release (57 ). crease twofold before a meal and decrease to trough
The activation of GHS-Rs by ghrelin on NPY/agouti- concentrations within 1 h after eating. In cases in which
related peptide (AGRP)-producing neurons located in the negative energy balance is typically observed, such as
arcuate nucleus stimulates food intake (58 ). Ghrelin in- low-calorie diets, chronic exercise, cancer anorexia, an-
creases fat tissue by decreasing fat oxidation. Stimulation orexia nervosa, and Prader–Willi syndrome, the most
of motility and gastric emptying induced by ghrelin may common form of human syndromic obesity, ghrelin con-
involve a local effect as well as central mechanisms (59 ). centrations were reported to be increased (65 ). In human
Ghrelin is much more than simply a natural GH obesity, the ghrelin concentration is low, which may be
secretagogue, however. It also acts on other central and related to the high caloric intake, whereas a reduction in
peripheral receptors and exhibits other actions, including body weight in obese patients brings the ghrelin concen-
stimulation of lactotroph and corticotroph secretion; it tration up. Interestingly, although ghrelin concentrations
also influences gastroenteropancreatic functions and has are reported to be high in patients undergoing diets,
orexigenic, metabolic, cardiovascular, and antiprolifera- stomach-bypass surgery decreased ghrelin concentra-
tive effects (60 – 62 ). tions, suggesting that the size of the stomach may be
Studies established that ghrelin stimulates food intake directly correlated to ghrelin concentrations (66 ). Several

Fig. 2. Action of ghrelin on adipose tissue and the brain.

experimental observations have suggested that the ghre- associated with ghrelin concentrations, which may consti-
lin is a strong gastrokinetic agent (67 ). tute part of a feedback mechanism by which body weight
is regulated in humans (73 ).
Endocrine signal to the hypothalamus. The arcuate nucleus is Anorexia nervosa is associated with high concentra-
a major hypothalamic site regulating food intake and tions of GH and low concentrations of insulin-like growth
body weight through the presence of neurons containing factor-1 (IGF-1), suggestive of a nutritionally acquired
orexigenic (NPY and AGRP) and anorexic (pro-opiomela- lack of GH action or GH resistance. Although ghrelin
nocortin and cocaine amphetamine-regulated transcript) values are higher in patients with anorexia nervosa than
peptides. In the brain, the GHS-R gene is abundantly in controls, there is no relationship between ghrelin and
expressed in the hypothalamic arcuate nucleus and ven- GH values. The inability of healthy girls to uniformly
tromedial nucleus. Existing evidence supports a key role suppress GH concentrations to 1 ␮g/L or less, a “normal
of the Arc nucleus in the orexigenic effects of ghrelin (68 ), concentration” defined for adults may be related to higher
but its regulatory effect on appetite is not essentially GH secretion in pubertal years compared with adult life
related to GH release (69 ). (74 ).
The pathways through which gastric ghrelin released The decrease in ghrelin over childhood and with
into the bloodstream signals the hypothalamus are not puberty does not suggest that it is a direct growth-
clearly understood. There is anatomic evidence derived promoting hormone. However, in view of the relationship
from studies on the capillary network in the Arc nucleus with IGF-1 and the positive relationship with IGF-binding
that part of the parenchyma in this nucleus can be protein-1, this decrease in ghrelin could facilitate growth
exposed to circulating neuroactive substances. Pharmaco- acceleration over puberty (75 ).
kinetic studies in mice also showed that human ghrelin There is a possible link between glucose concentrations
crosses the blood– brain barrier as an intact molecule by and ghrelin; hence, the persisting low ghrelin concentra-
saturable transport. Although passage for des-octanoyl tions in diabetic children may suggest a defensive mech-
mouse ghrelin was observed in the blood-to-brain direc- anism against hyperglycemia (76 ).
tion, the octanoylated (bioactive) mouse ghrelin crosses The observation that ghrelin is further decreased in
the mouse barrier predominantly in the brain-to-blood cases of abnormal energy profit adds new evidence to the
direction. The extent and direction in which ghrelin can relationship between ghrelin activity and energy balance
cross the blood– brain barrier is therefore influenced by at in obesity (77 ). Circulating ghrelin concentrations are
least two features of its primary structure: its posttrans- influenced by body fat distribution, but not by concentra-
lationally added fatty acid side chain and its amino acid tions of either GH or IGF-1. However, given that obesity
sequence (70 ). is associated with reduced ghrelin concentrations and that
GH deficiency is commonly associated with increased
analytical aspects body fat, it is possible that these two opposing influences
Several assays are available to measure human ghrelin. on circulating ghrelin concentrations produce normal
Linco Research, Inc. (71 ) introduced a system for analyz- concentrations in individuals with GH deficiency (78 ).
ing the so-called “active” human ghrelin (lower limit of
detection, 10 ng/L; linear range, 10 –2000 ng/L; intraassay clinical significance
CV ⫽ 7.4%; interassay CV ⫽ 13.5%). The antibody was Ghrelin has profound orexigenic, adipogenic, and soma-
raised against a human ghrelin epitope carrying an oc- totropic properties, increasing food intake and body
tanoyl group on the serine-3 position, which determines weight. Secreted predominantly from the stomach, ghre-
the biological function of the hormone by enabling bind- lin is the natural ligand for the GHS-R in the pituitary
ing to the receptor. To perform this analysis, however, gland, thus fulfilling the criteria of a brain– gut peptide.
special precautions must be taken, such as acidification of The brain– gut axis is the effector of anabolism by regu-
the sample to stabilize the labile side chain. Because a lating growth, feeding, and metabolism via vagal afferent-
majority of studies performed at present refer to samples mediating ghrelin signaling. However, the wide tissue
that have been collected and stored without fulfilling distribution of ghrelin suggests that it may have other
these requisites, the investigations are focused on those functions as well. It also enhances immune responses and
assays designed for the analysis of total ghrelin in human potentially down-regulates antiinflammatory molecules.
serum. It is likely, however, that measurement of the The role of ghrelin as a brain– gut peptide emphasizes the
physiologically active ghrelin portion may be more rele- significance of afferent vagal fibers as a major pathway to
vant. the brain, serving the purpose of maintaining physiologic
Serum ghrelin concentrations change in opposite direc- homeostasis. The discovery of ghrelin has increased our
tions in obesity and anorexia nervosa after dietary inter- understanding of feeding regulation, nutritional ho-
vention, suggesting that ghrelin is a good marker of meostasis, and metabolic processes. Further characteriza-
nutritional status (72 ). tion of the functions of ghrelin will likely generate new
The concentration is reduced in states of obesity. approaches to the diagnosis and treatment of different
Insulin resistance and hyperinsulinemia are inversely disease entities, including those related to the overnutri-
1518 Meier and Gressner: Endocrine Regulation of Energy

tion of obesity and the catabolic response to surgical of production or activity of proteins associated with
trauma (79 – 81 ). triglyceride metabolism, including CD36, acyl CoA oxi-
Ghrelin may have also cardioprotective effects, serve as dase, 5⬘-activated protein kinase, and peroxisome prolif-
a diagnostic or therapeutic tool in GH deficiency, and erator-activated receptor ␥ (PPAR␥) (88 ).
function as a marker for neuroendocrine tumors. Theoret- A negative correlation between obesity and circulating
ically, ghrelin is a promising candidate for treating cata- adiponectin has been well established, and adiponectin
bolic states and enhancing immune function in cachexia concentrations increase concomitantly with weight loss
or AIDS, as well as for treating eating disorders such as (89 ). Decreased adiponectin concentrations are associated
obesity and anorexia nervosa (82 ). with insulin resistance and hyperinsulinemia, and pa-
tients with type II diabetes are reported to have decreased
Adiponectin circulating adiponectin. Thiazolidinediones, a class of
structure and synthesis insulin-sensitizing antidiabetic drugs, increase adiponec-
Adiponectin, also known as adipocyte complement-re- tin in insulin-resistant patients. In addition, high adi-
lated protein of 30 kDa (ACRP30), adipoQ, adipose most ponectin concentrations are associated with a reduced
abundant gene transcript 1 (apM1), and gelatin-binding risk of type II diabetes (90 ). Magnetic resonance spectros-
protein of 28 kDa (GBP28), is an adipocyte-specific, se- copy has demonstrated that intracellular lipid content in
creted protein with roles in glucose and lipid homeostasis. human muscle negatively correlates with adiponectin
Circulating adiponectin concentrations are high (500 – concentrations, potentially because of adiponectin-in-
30000 ␮g/L), accounting for ⬃0.01% of total plasma duced fatty acid oxidation (91 ).
protein (83 ). Adiponectin contains a modular structure The synthesis and secretion of adiponectin is regulated
that includes an N-terminal collagen-like domain and a by several mechanisms (Fig. 3). Small adipocytes secrete
C-terminal globular domain with significant sequence insulin-sensitizing hormone, adiponectin, leptin, and
and structural similarities to the complement factor C1q. other hormone-like peptides. Adipocyte hypertrophy
Although they share little sequence identity, similar three- (large adipocytes), induced by a high-fat diet, causes
dimensional structure and certain conserved amino acid decreases in the production and secretion of insulin-
residues suggest an evolutionary link between the C1q- sensitizing hormone and increases in insulin-resistant
like domain of adiponectin and members of the TNF hormone, leading to insulin resistance in obesity. Reduc-
superfamily. Adiponectin assembles into homotrimers, tion in the activity of PPAR␥, which belongs to the nuclear
and higher-order oligomeric structures are formed by hormone receptor superfamily, leads to protection against
interactions between the collagen-like regions (84 ). Adi- obesity and type II diabetes induced by a high-fat diet.
ponectin is induced during adipocyte differentiation, and Adiponectin decreases lipid synthesis and glucose pro-
its secretion is stimulated by insulin. Two receptors for duction in the liver and causes decreases in glucose and
adiponectin, termed AdipoR1 and AdipoR2, have been free fatty acid concentrations in the blood. In addition,
cloned (85 ). Although functionally distinct from G-pro- triglyceride production is decreased and fat oxidation and
tein-coupled receptors, the genes encode predicted pro- energy dissipation in the muscle are increased.
teins containing seven transmembrane domains. AdipoR1 Both insulin and IGF-1 increase adiponectin synthesis
is produced primarily in skeletal muscle, whereas Adi- in white adipose tissue. The synthesis and secretion of
poR2 is primarily found in hepatic tissues. Recently, adiponectin are decreased in the presence of caloric
T-cadherin was identified as a receptor for the hexameric excess, presumably associated with leptin deficiency or
and high-molecular-weight species of adiponectin. It may resistance (92 ). The protein can also increase the sensitiv-
act as a coreceptor for a signaling receptor through which ity of the hepatocyte to insulin, either through direct
adiponectin transmits metabolic signals (86 ). action or indirectly by lowering circulating lipids concen-
trations via its action on muscle. Thus, administration of
functions adiponectin can lead to improved insulin sensitivity and
Metabolic effects. Injection of adiponectin into nonobese glucose tolerance and can correct the hyperglycemia
diabetic mice leads to an insulin-independent decrease in associated with obesity.
glucose concentrations. This is likely attributable to insu-
lin-sensitizing effects involving adiponectin regulation of Pharmacologic effects. Chronic treatment with the PPAR␣
triglyceride metabolism (87 ). A truncated form of adi- agonist rosiglitazone reduces adiponectin production in
ponectin (gAdiponectin) containing only the C-terminal obese db/db mice, which lack functional leptin receptors
globular domain has been identified in the blood, and (93 ). In contrast, Maeda et al. (94 ) observed that thiazo-
recombinant gAdiponectin has been shown to regulate lidinediones, which are PPAR␥ agonists, stimulate adi-
weight reduction as well as free fatty acid oxidation in ponectin gene expression and increase circulating adi-
mouse muscle and liver. The full-length recombinant ponectin concentrations in obese mice and insulin-
adiponectin protein is apparently less potent at mediating resistant obese humans. Because adiponectin improves
these effects. The mechanism underlying the role of glucose tolerance by increasing insulin sensitivity, the
adiponectin in lipid oxidation may involve the regulation effect of thiazolidinediones on adiponectin secretion may
 Clinical Chemistry 50, No. 9, 2004 1519

Fig. 3. Action of adiponectin on adipose tissue and peripheral organs (liver, blood, and skeletal muscle).

explain, at least partially, the hypoglycemic effect of these ponectin-deficient mice and is inhibited by exogenous
drugs in patients with type II diabetes mellitus. adiponectin (101 ). Adiponectin inhibits endothelial cell
TNF-␣ produced by white adipose tissue is markedly production of adhesion molecules in vitro, suppressing
up-regulated in obesity and contributes to insulin resis- the attachment of monocytes. In addition, adiponectin
tance by interfering with insulin receptor signaling (95 ). negatively regulates myelomonocytic progenitor cell
This cytokine suppresses adiponectin production in adi- growth and TNF-␣ production in macrophages (102 ).
pose tissue, whereas thiazolidinediones prevent this in- Recent investigations of Kamada et al. (103 ) demon-
hibitory effect of TNF-␣ (96 ). The pharmacologic effect of strated that carbon tetrachloride induces extensive liver
adiponectin in reducing insulin resistance has been re- fibrosis in adiponectin knockout mice. Conversely, injec-
lated to a decrease in plasma fatty acid concentrations and tion of an adenovirus that produces adiponectin before
in triglyceride content in mice models of obesity, but also carbon tetrachloride treatment prevented liver fibrosis,
in human hyperlipidemia. Adiponectin can improve fatty and in cultured profibrogenic hepatic stellate cells, adi-
acid catabolism either directly or by stimulating the ponectin suppressed platelet-derived growth factor-in-
production of PPAR␣, which regulates the enzymes in- duced proliferation and attenuated the effect of TGF-␤1
volved in lipid metabolism (97–99 ). and connective tissue growth factor.
Low plasma adiponectin concentrations have been
Atherosclerotic effects and adhesion. Adiponectin may also reported in coronary artery disease as well as associated
play antiatherogenic and antiinflammatory roles. Plasma with some risk factors of cardiovascular disease, such as
adiponectin concentrations are decreased in patients with male sex, high blood pressure, obesity, and type II diabe-
coronary artery disease (100 ). Furthermore, neointimal tes mellitus. Adiponectin has been shown to reduce the
thickening of damaged arteries is exacerbated in adi- secretion of TNF-␣ from monocyte/macrophages and
1520 Meier and Gressner: Endocrine Regulation of Energy

foam cells and also to attenuate the biological effects advantageous in reversing insulin resistance in lipodys-
induced by TNF-␣. In fact, this protein suppresses the trophic disorders and metabolic syndrome (114 ).
secretion of TNF-␣ (104 –106 ). The antiinflammatory effects of adiponectin indicate
Taken together, these data suggest that this adipocyte- that it is an interesting protective factor for atherosclerosis
derived cytokine may exert antiinflammatory, antifi- development, particularly in those clinical situations as-
brotic, and antiatherogenic effects, particularly in endo- sociated with low plasma concentrations of adiponectin. It
thelial cells and macrophages; it therefore seems to play a is conceivable that the use of recombinant adiponectin
protective role in experimental models of vascular injury may become beneficial in the prevention of cardiovascu-
as well as in the early events in the atherosclerotic process. lar disease in selected patients.
Data suggest that increasing plasma adiponectin might
analytical aspects be useful in preventing vascular restenosis after vascular
Competitive RIAs and sandwich ELISAs are available to intervention (115 ). Further investigations in patients with
measure human adiponectin: the RIA (Linco Research, the above-mentioned states and other hypoadiponectine-
Inc.) has a lower limit of detection of 1 ␮g/L and a linear mic conditions are required to clarify these aspects of the
range of 0.78 –200 ␮g/L (intraassay CV ⫽ 4%; interassay potential therapeutic applications of this adipocytokine.
CV ⫽ 8%); the ELISA (R&D Systems) has lower limits of
detection of 0.079 – 0.891 ␮g/L and a linear range of Resistin
3.9 –250 ␮g/L (intraassay CV ⫽ 3.5%; interassay CV ⫽ structure and synthesis
6.5%) (107 ). Serum adiponectin concentrations were high Human resistin, a 12.5-kDa protein, contains 108 amino
in constitutionally thin individuals and low in obese acids as a prepeptide, and its hydrophobic signal peptide
individuals. The insulin resistance was significantly lower is cleaved before its secretion. Resistin circulates in hu-
in anorexia nervosa and high in obese individuals. The man blood as a dimeric protein consisting of two 92-
concentrations of adiponectin after weight recovery in- amino acid polypeptides that are linked by a disulfide
bridge (116 ) at Cys-26. Holcomb et al. (117 ) first described
creased to within reference values despite a relatively
the gene family and its tissue-specific distribution. By
small increase in BMI. These findings suggest that abnor-
comparison of bronchoalveolar lavages from control mice
mal feeding behavior in patients with eating disorders
with lavages from mice subjected to experimentally in-
may lead to a decrease in circulating adiponectin concen-
duced asthma, they identified, by microsequencing, a
tration and that weight recovery can restore it (108 ).
protein that was up-regulated in the asthmatic lung. This
In humans, the plasma adiponectin concentration neg-
novel protein, FIZZ1 (found in inflammatory zone 1) is
atively correlates with BMI, percentage of body fat, fast-
also known as resistin-like molecule ␣ (RELM␣). One of
ing insulin concentration, and plasma triglycerides but
two additional homologs, FIZZ2, also known as RELM␤,
positively with the plasma cholesterol contained in HDL
was found to be localize in proliferating epithelia at the
(109 ). Moreover, surgical treatment of morbid obesity by
base of the crypts in the intestinal tract. Steppan et al.
gastric partition surgery leads to an increase in plasma (118 ) later provided supporting data that FIZZ2/RELM␤
adiponectin concentration, which is significantly corre- is also present in rapidly dividing epithelia by demon-
lated with body weight reduction. Weight reduction strating a marked increase in intestinal tumors compared
achieved by low-calorie diet also increases plasma adi- with control epithelia. RELM, originally described as lung
ponectin in both nondiabetic and diabetic patients (110 ). specific, is also produced in adipose tissue.
The adiponectin concentration is lower in patients with The third homolog, FIZZ3, is known as resistin or
impaired glucose tolerance or type II diabetes mellitus adipocyte-specific secretory factor and is identical to the
than in age- and BMI-matched individuals with normal fat specific homolog (119 ). Steppan et al. (120 ) have
glucose tolerance and correlates negatively with plasma subsequently proposed that resistin is increased in type II
glucose measured at 2 h in the oral glucose tolerance test diabetes and suggested that it is a potential link between
(111 ). obesity and insulin resistance. The injection of recombi-
nant resistin into mice reduces glucose tolerance and
clinical significance insulin action, whereas neutralization with anti-resistin
Increased serum adiponectin concentrations are associ- antibodies improves insulin action.
ated with increased insulin sensitivity and glucose toler-
ance (112 ). It can therefore be speculated that adiponectin, functions
or drugs that stimulate adiponectin secretion or action, Very little is known about the potential function of
could play a role in disease states combined with insulin resistin or its homologs (121 ). As fat cells (adipocytes)
resistance, mainly type II diabetes mellitus, metabolic store more fat molecules and enlarge, they release several
syndrome, and obesity. Low concentrations of adiponec- products that can modify the body’s sensitivity to insulin.
tin have also been implicated in the severe insulin resis- Free fatty acids and TNF-␣ cause insulin resistance, and
tance that accompanies lipoatrophy in both animal mod- leptin, which regulates energy balance, probably causes
els and humans (113 ). Therapy with adiponectin may be insulin sensitivity. Thiazoladinedione drugs reduce insu-
 Clinical Chemistry 50, No. 9, 2004 1521

lin resistance and are used to treat type II diabetes. These of recombinant resistin and RELM␤ to rats led to acutely
drugs suppress the production of resistin by adipocytes, impaired hepatic insulin sensitivity and glucose metabo-
and their antidiabetes effects may, at least in part, be lism. The primary pathway underlying changes in hepatic
achieved through this mechanism (Fig. 3). glucose metabolism appears to be increased glucose pro-
Initial studies have demonstrated that obesity induced duction. Interestingly, no effect was observed on periph-
by a high-fat diet, mutation of the leptin gene (ob/ob eral glucose disposal under the clamp conditions, effec-
mice), or mutation in the leptin receptor gene (db/db tively ruling out a role for resistin in this part of the
mice) is associated with increased circulating resistin insulin action, at least under the experimental paradigms
concentrations. Resistin increases blood glucose and insu- used in the study. This was a straightforward examination
lin concentrations in mice and impairs hypoglycemic of the acute effects of resistin and RELM␤ on insulin
response to insulin infusion. In addition, anti-resistin action, and the results are quite clear. The findings also
antibodies decrease blood glucose and improve insulin suggest that resistin, and the closely related RELM␤, may
sensitivity in obese mice (122 ). Resistin suppresses insu- act to establish links among adipose tissue, the intestine,
lin-stimulated glucose uptake in cultured 3T3-L1 adipo- and the liver. It now remains to be determined whether
cytes, and this effect is prevented by anti-resistin anti- these pathways are operational under physiologic or
bodies. These data suggest that resistin induces insulin pathophysiologic conditions.
resistance and that hyperresistinemia contributes to im-
paired insulin sensitivity in obese rodents (123 ). The analytical aspects
suppressive effect of thiazolidinediones on resistin secre- Some sandwich ELISAs are available to measure human
tion found in some studies may contribute to the insulin- resistin: the Biovendor assay has a lower limit of detection
sensitizing effect of this class of drugs. However, other of 0.2 ␮g/L and a linear range of 1–50 ␮g/L (intraassay
data do not confirm these results. Way et al. (124 ), Moore CV ⫽ 4.7%; interassay CV ⫽ 8%) (132 ), and the R&D
et al. (125 ), and Le Lay et al. (126 ) observed lower resistin Systems assay has lower limits of detection of 0.01– 0.055
mRNA in adipose tissue in different models of mouse ␮g/L and a linear range of 0.16 –100 ␮g/L (intraassay
obesity, such as diet-induced obesity, and in rat models CV ⫽ 4.7%; interassay CV ⫽ 8.4%). Plasma leptin and,
characterized by hyperinsulinemia, hyperglycemia, hy- probably, resistin concentrations are decreased in anorec-
pertriglyceridemia, and hypertension. tic patients, whereas plasma adiponectin concentrations
The physiologic role of resistin in humans remains are increased. These alterations may have potential reper-
unknown. Given the incomplete homology between hu- cussions in the pathophysiology of anorexia nervosa.
man and mouse resistin and the absence in humans of one Thus, low leptin and high adiponectin may separately or
of the three murine resistin isoforms, resistin in humans in concert contribute to altered hematopoiesis and immu-
may have a different physiologic role than that in mice. nity, enhanced insulin sensitivity, neuroendocrine distur-
Studies of genetic variations in the resistin gene, including bances, or osteopenia in anorexia nervosa (133 ).
single-nucleotide polymorphisms, are controversial re- In healthy populations, a correlation was found be-
garding the role of resistin in obesity and insulin sensi- tween leptin and resistin concentrations in serum. In
tivity. Moreover, resistin mRNA expression is very low in patients with severe inflammatory disease, a correlation
isolated human adipocytes and does not correlate consis- between resistin concentration and laboratory markers of
tently with insulin resistance or obesity, making the role inflammation was shown; however, no correlation was
of human resistin in insulin resistance unclear (127, 128 ). found between leptin and resistin. Serum resistin concen-
There is no correlation between body weight, adipos- trations in these patients were significantly higher than in
ity, and insulin resistance and resistin mRNA concentra- healthy individuals and persons with well-controlled type
tion. Resistin is produced in the stromovascular fraction 2 diabetes mellitus with signs of insulin resistance. This
of adipose tissue and in peripheral blood monocytes. may be attributable to a direct effect of inflammatory
Species differences in cellular resistin distribution may be cytokines on resistin production. In persons with type 2
partially explained by recent observation that in humans, diabetes mellitus, no significant correlations were found
in contrast to rodents, resistin is produced in high con- between resistin and other individual characteristics (in-
centrations in cultured preadipocytes but barely detect- sulin sensitivity markers, BMI, or leptin). Resistin concen-
able in mature fat cells (129 ). Thus, the role of resistin and trations in persons with type 2 diabetes mellitus do not
other members of the FIZZ/RELM family in humans differ from concentrations in the general population (131 ).
remains to be established. These proteins may be involved
in the regulation of cell proliferation and differentiation. clinical significance
Given the production of FIZZ1/RELM␣ in inflammatory The role of resistin in obesity and insulin resistance in
regions and of resistin in inflammatory cells, another humans is controversial. There is more serum resistin
possibility is their involvement in chronic inflammatory protein in obese than lean individuals, with a significant
reactions associated with obesity (130 ). positive correlation between resistin and BMI. BMI is a
Rajala et al. (131 ) provided clarification of the biolog- significant predictor of insulin resistance, but resistin
ical functions of the FIZZ/RELM family. Administration adjusted for BMI is not. These data demonstrate that
1522 Meier and Gressner: Endocrine Regulation of Energy

resistin protein is present in human adipose tissue and Several assays (competitive RIA and sandwich ELISA)
blood and that there is significantly more resistin in the have been developed by many manufacturers to measure
serum of obese individuals. Serum resistin is not a signif- leptin, its receptor, ghrelin, adiponectin, and resistin. All
icant predictor of insulin resistance in humans (132, 133 ). assays have good performance regarding detection limits,
linearity, and precision. Leptin, its receptor, adiponectin,
Summary and resistin are stable, in contrast to ghrelin, which is
The newly discovered secretory function of the adipo- labile and measured under difficult conditions. The con-
cytes has shifted the view of the white adipose tissue from centrations of all of these hormones depend of the BMI.
a simple energy storage tissue to a major endocrine
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