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Original Studies |
Department of Endocrinology and Metabolism, Gulhane School of Medicine (M.O., I.C.O.), Etlik-Ankara 06018, Turkey; and the Clinical Neuroendocrinology Branch, National Institute of Mental Health, National Institutes of Health (J.L.), Bethesda, Maryland 20892-1284
Address all correspondence and requests for reprints to: Julio Licinio, M.D., UCLA Department of Psychology, 3554 Gonda Center, 695 Charles Young Drive South, Los Angeles, California 90095. E-mail: licinio{at}ucla.edu
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Abstract |
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Introduction |
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Homozygous or compound heterozygous mutations in leptin (13, 14), leptin receptor (15), melanocortin-4 receptor (16, 17), POMC (18), and prohormone convertase 1 gene (19) have been found in association with human obesity. However, it is still undetermined what the similarities and differences are among the phenotypes associated with those mutations. A new direction for research in the field of human obesity would be the characterization of genotype-phenotype correlations in monogenic human obesity. Such studies would permit the differentiation of the clinical and biochemical consequences of obesity from the effects of specific genes that have pleiotropic functions, involving not only the regulation of food intake, energy expenditure, and body weight, but also directly or indirectly modulating the functions of multiple organs and systems. We have previously demonstrated a missense mutation in the leptin gene of a highly consanguineous Turkish family (13). Our previous observations demonstrated that congenital leptin deficiency is associated with hypogonadotropic hypogonadism and morbid obesity. We have now performed detailed clinical and laboratory assessments in this family to characterize the effects of genetic leptin deficiency on several endocrine functions in childhood and adulthood. The other families previously reported with mutations in either the leptin gene or the leptin receptor gene have only homozygous children or adult homozygous females. The presence of both a child and adults of both sexes in this family makes this the first analysis of the effects of genetically mediated leptin deficiency in childhood and in adult men and women.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Clinical protocols
TRH test. The TRH test uses a single iv dose of 400 µg synthetic TRH (pediatric dose, 7 µg/kg). Blood samples are collected at 0, 15, 20, 30, 60, and 120 min. for determination of serum TSH and PRL. In normal individuals, a prompt rise in TSH observed at 15–20 min is 3–5 times the basal level or, on the average, 16 IU/L. Serum TSH declines after 30 min and returns to the preinjection level at 180 min. A PRL rise of at least 2–3 times basal levels and a peak greater than 20 ng/mL, occurring at 30 min, are seen in normal individuals.
GnRH test. A single dose of synthetic GnRH (100 µg) is administered by rapid iv injection after an overnight fast. Blood samples are obtained at 0, 15, 30, 45, 60, and 120 min for determination of serum LH and FSH concentrations. LH peaks up to 5-fold the basal value at 15–30, and serum FSH rises to about 2-fold the basal value at 45–90 min after an iv injection of GnRH in normal individuals.
Insulin-induced hypoglycemia. This is a stimulus to GH secretion. In adult patients, regular insulin (0.15 U/kg BW) is injected as an iv bolus, and blood samples for plasma glucose and GH determinations are obtained at 0, 30, 60, and 90 min. Plasma glucose should be reduced to levels below 40 mg/dL, and symptoms of hypoglycemia should be present. A normal response involves a rise in serum GH by at least 5 ng/mL above baseline or to an absolute level of more than 10 ng/mL.
Upright posture-PRA stimulation test. Assumption of an erect posture after a prolonged supine position induces renin secretion. Patients should be on restricted sodium intake (10 mEq/day) for 3 days. On the third day, after a quiet night sleep (horizontal position for a minimum of 5 h), a blood sample for PRA determination is obtained. The patient is encouraged to ambulate actively for 3–4 h, and then a second blood sample is obtained. A normal response consists of a mean increase in PRA over supine values of 142%.
Cold pressor test. After 15 min of bed rest, the basal blood pressure is measured, and the right arm of the subject up to the elbow is immersed in ice water at 4 C and kept in ice water for 1 min. During this time two blood pressure measurements from the left arm are performed. This procedure is repeated four times in each patient on separate days. Maximal elevations of systolic and diastolic blood pressures from the baseline are accepted as cold pressor responses.
Oral glucose tolerance test. This is performed after fasting of not less than 10 h or more than 16 h. The test is performed in the morning while the patient is seated. A load of 75 g oral D-glucose (dextrose) in 300 mL distilled water is administered within 5 min. Blood specimens are obtained for plasma glucose and insulin determinations at 0, 30, 60, 90, and 120 min from the beginning of the glucose load.
Exercise tolerance test. This is performed using a bicycle ergometer, and blood samples are drawn at baseline and when the work load results in a pulse rate of 180 beats/min.
Postural hypotension test. After 15 min of bed rest, blood pressure measurements are made while the subject is lying and standing for 1 min. The differences between the measurements are calculated. Postural hypotension is defined as a fall in systolic blood pressure of 30 mm Hg or more, immediately after standing, with a borderline zone of 11–29 mm Hg. This procedure is repeated four times in each patient on separate days.
The percentage of body fat was determined using a bioelectrical impedance device (Bodystat 1500, Bodystat Limited, Douglas, UK).
Hormone analyses
Free T4, free T3, TSH, FSH, LH, PRL,
cortisol, total testosterone, ACTH, estradiol, free testosterone,
progesterone, and insulin were measured by chemiluminescent enzyme
immunoassay (a solid phase, two-site sequential chemiluminescent
immunometric assay) using commercial kits from Chiron Corp. (East Walpole, MA). Sex hormone-binding globulin was
measured by immunoradiometric assay (SHBG IRMA 125 I kit, RADIM S.A.
Angleur, Liege, Belgium). Antithyroid peroxidase was measured by RIA
(DYNOtest anti-TPOn kit, BRAHMS Diagnostica, Gmbh, Berlin, Germany).
Aldosterone and 17
-hydroxyprogesterone were measured by RIA using
kits from Diagnostics Systems Laboratories, Inc. (Webster,
TX). GH and PTH were measured by RIA using kits from Diagnostic Products (Los Angeles, CA). DHEAS was measured by RIA using
DHEAS ImmuChem Coated Tube kits (ICN Biomedicals, Inc.,
Costa Mesa, CA). Leptin was measured by RIA using a commercially
available kit (Linco Research, Inc., St. Charles, MO) with
a detection limit of 0.5 ng/mL. Renin was measured by chemiluminescent
enzyme immunoassay using kits from DiaSorin, Inc.
(Dusseldorf, Germany). Weight and height measurements were recorded.
Blood samples were drawn after an overnight fast and analyzed
immediately. Blood glucose was measured using the enzymatic
colorimetric method by glucose oxidase on an RA-1000
autoanalyzer. Total cholesterol was measured by the
CHOD-PAP method using Menagent Cholesterol-HF kits (Menarini
Diagnostics, Florence, Italy). Triglycerides were measured by the
enzymatic colorimetric method using Menagent Triglycerides kits
(Menarini Diagnostics). Total calcium was measured by the
0-Cresolphthalein Complexone method using calcium (Procedure 587) kits
(Sigma Chemical Co., St. Louis, MO). Ionized calcium was
measured by ion-selective electrode on an AVL 988–3 ISE electrolyte
analyzer (AVL Medical Instrument A.G., Schaffhausen, Switzerland).
Magnesium was measured by the calmagite complexion method using
Menagent Magnesium 60-s. kits (Menarini Diagnostics). Phosphorus was
measured by the ammonia molibdate complex method using Menagent
Phosphofix kits (Menarini Diagnostics). High density lipoprotein
cholesterol (HDL-C) was measured using kits from Menarini Diagnostics.
Low density lipoprotein cholesterol (LDL-C) and very low density
lipoprotein (VLDL) were calculated using Friedman’s formula.
Lymphocyte subpopulations were analyzed using specific monoclonal
antibodies from Becton Dickinson and Co. (Meylin, France)
on FACSCalibur Flow Cytometry (Becton Dickinson and Co.,
San Jose, CA). Igs and C3c and C4 were measured by an
immunonefelometric method, using antisera from Behring GmbH (Marburg,
Germany).
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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). This new homozygous patient is also
severely obese and amenorrheic. As expected, her normal weight father
and mother are heterozygous. Detailed historical analysis showed that 1
brother of male homozygous patient (patient 47), 3 brothers of female
homozygous patient (patient 23), and 1 sister and 2 brothers of this
newly identified homozygous patient (patient 40) died in early
childhood. Thus, in the youngest generation of this family there are 19
individuals who are normal weight, with no mortality among those.
However, of 11 individuals born with the obese phenotype described in
this article and brought up in the same locality and under the same
social and nutritional conditions with access to the same medical
services as their normal weight relatives, 7 died in childhood during
the course of infections, and only 4 (described in this article) are
alive now. A Yates 
2 test showed that this number of
deaths is significantly higher than expected (P <
0.01) based on the null hypothesis that a leptin gene mutation does not
predispose to death in childhood. The odds ratio was estimated to be
25.4, and the 95% confidence limits of this ratio were 1.8 and 124.5.
Thus, normal weight subjects in this family are 25.4 times more likely
to be alive than their obese relatives.
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. Hypogonadism is a clinical feature of
all three adult homozygous patients. This appears to be a defect at the
hypothalamic level, because all three adult patients (Table 2) demonstrated normal gonadotropin
responses to GnRH stimulation. The male homozygous patient (patient 47)
never entered puberty and had clinical features of hypogonadism. He has
no beard, scanty hair in the pubic and axillary area, bilateral
gynecomasty, small penis, small testis size, and azospermia (stretched
penile length, 5 cm; right testis in the inguinal channel, volume, 3.67
mL; left testis in the scrotum, volume, 4.09 mL; normal range, 20–30
mL). His recent free and total testosterone level measurements were low
(Table 1). The newly identified female homozygous patient (patient 40)
had normal karyotype (46,XX). She had reported scanty menstrual
bleeding every 7–8 months since age 29 yr, which does not appear to
represent physiological menstrual function. Physical examination showed
scarce hair in the pubic and axillary area. Ultrasound of the mammary
glands showed that they consist solely of adipose tissue. Ultrasound
also demonstrated that the dimensions of her uterus are 25 x
35 x 70 mm. Both ovaries had normal localization; the dimension
of the right ovary was 16 x 11 mm, and that of the left ovary was
19 x 12 mm. Her 17-hydroxyprogesterone (17-OHP) and progesterone
levels were low. The female homozygous patient whom we previously
reported (13) (patient 23) had primary amenorrhea until March 1998.
However, for the last 9 months she has menstruated regularly and
entered puberty. Her hormone levels during a menstrual cycle are shown
in Table 3. This appears to
reflect a luteal phase defect, as 1 week before the onset of
menstruation, her plasma progesterone levels were less than 10–12
ng/mL (20). Pelvic ultrasound of this patient demonstrated that her
uterus is 73 x 50 x 30 mm (normal size, 70–80 x
50–60 x 40–50 mm) in diameter, her left ovary is 18 x 12
mm (normal size, 25–50 x 15–30 mm), and her right ovary is
8.9 x 10.2 mm. Her pubic and axillary hair growth is normal.
However, mammary gland ultrasound showed that the majority of the
glands consisted of adipose tissue with a small amount of glandular
tissue. Electroencephalogram and sella computerized tomography were
normal. Pelvic ultrasound of the homozygous female child (patient 54)
demonstrated that dimensions of her uterus were 20 x 10 x 6
mm in diameter; her ovaries could not be observed by ultrasound.
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. All homozygous patients have high
plasma C3C levels. The homozygous child has low
C4 levels. The adult female patients have elevated IgG and
IgA levels. However, the homozygous child has a low total T cell
count.
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and 6).
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); however, BMD of the spine showed osteopenia [BMD of L2–L4, 0.924
g/cm2; bone mineral content (BMC), 52.60 g;
t-score, -1.96; z-score, -2.36]. In contrast, patient 40
exhibited high PTH levels on repeated measurements, several days apart
(183, 209, and 242 pg/mL; normal, 12–72). Her total calcium levels and
ionized calcium levels were also low (Table 1). Her urinary calcium was
likewise below normal limits (51.6 mg/24 h; normal, 100–300 mg/24 h).
Repeated calcium measurements also demonstrated low plasma calcium
levels. She had normal BMD (BMD of L2–L4, 1.042 g/cm2;
BMC, 46.049; t-score, 0.0; z-score, -0.17), and x-rays of
the extremities showed no sc ossification and no short metatarsals in
the hand. Patient 23 had PTH levels in the upper normal range (71.9
pg/mL), a normal calcium level, and normal BMD (BMD of L2–L4, 1.185
g/cm2; BMC, 54.47 g; t-score, 1.23; z-score,
1.06). The homozygous female child (patient 54) had high PTH levels
(Table 1), but her plasma ionized calcium level was normal. We did not
find any abnormalities in PTH-calcium in any heterozygous or wild-type
member of the family.
Thyroid function was abnormal in the child and normal in the adult
patients. The homozygous girl (patient 54) had high plasma TSH levels,
as shown in Table 1 (TSH, 6.0 IU/L; normal, <5.5). Antithyroid
antibodies were negative. Repeated thyroid function tests 7 months
later were as follows: free T3, 3.7 pg/mL; free
T4, 1.1 ng/mL; and TSH, 9.4 IU/L. Her TRH stimulation test
was indicative of hypothyroidism (Table 2). This child appears to have
subclinical hypothyroidism. In contrast, the adult homozygous
individuals (patients 23, 40, and 47) had normal TSH and PRL responses
to a TRH stimulation test (Table 2). Thus, among four homozygous
patients, only the 7-yr-old female child’s TSH levels were elevated,
and only her TSH response to TRH administration was exaggerated.
Basal cortisol and ACTH levels were higher in patients 40, 23,
and 54. All four homozygous patients had normal free urinary cortisol
concentrations. The administration of 1.0 mg dexamethasone at 2300
h reduced plasma cortisol concentrations to less than 5.0 µg/dL at
0800 h in all homozygous patients. Diurnal ACTH and cortisol
concentrations are shown in Table 7.
Moreover, as shown in Tables 1 and 3, the adult homozygous patients
have low 17-OHP concentrations; however, the child’s 17-OHP
concentrations are normal.
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As shown in Table 1, hematological parameters were normal in the
leptin-deficient subjects, but they were abnormal in patients 34, 22,
and 41, who had severe anemia (Table 6). Blood analysis of patient 22
showed severe hypochromic, microcyte anemia. Her reticulocyte level was
1.0%, and her plasma ferritin level was low (<0.5 ng/mL; normal
range, 10–291 ng/mL). Patient 41 also had iron deficiency (ferritin,
7.3 ng/mL).
Despite their severe obesity, we have observed that our leptin-deficient subjects exhibited mildly elevated fasting triglycerides concentrations; however, their cholesterol, LDL-C, and VLDL levels were in the normal range, and their HDL-C levels were at the lower limit of the normal range. These data would support the hypothesis that leptin might contribute to the hyperlipidemia of obesity.
Patient 23 had a fasting blood glucose level of 160 mg/dL in
September 1997. In March 1998, a glucose tolerance test was performed;
the results are listed in Table 2. However, in September 1998, her
glucose levels after a 75-g glucose load were as follows: fasting, 100
mg/dL; at 30 min, 152 mg/dL; at 60 min, 174 mg/dL; at 90 min, 176
mg/dL; and at 120 min, 156 mg/dL. We have previously reported (13) that
the fasting blood glucose level in an adult homozygous woman was 160
mg/dL. However, at the present time her oral glucose tolerance test and
fasting blood glucose levels are normal. This might be due to changes
in diet after the first measurement. We could not find at the present
time abnormalities in glucose homeostasis in homozygous or heterozygous
subjects. As listed in Table 2, oral glucose tolerance tests showed
normal glucose and insulin responses in the obese leptin-deficient
subjects.
Sympathetic system dysfunction (low sympathetic tone) was present in all 4 leptin-deficient subjects. In response to the cold pressure response test patient 47 showed a systolic blood pressure response of 7.2 ± 0.16 mm Hg and a diastolic blood pressure response of 6.95 ± 0.12 mm Hg; likewise, this subject had abnormal responses to an orthostatic hypotension test (fall in blood pressure from 132.5 ± 2.88/95.0 ± 4.08 mm Hg to 91.2 ± 2.5/61.2 ± 2.5 mm Hg after standing for 1 min) (22). In response to the cold pressor response test patient 23 showed a systolic blood pressure response of 7.62 ± 0.12 mm Hg and a diastolic blood pressure response of 7.2 ± 0.13 mm Hg after forearm immersion in ice-cold water for 1 min; likewise, this subject had abnormal responses to an orthostatic hypotension test (fall in blood pressure from 123.7 ± 2.9/72.5 ± 2.8 mm Hg to 88.7 ± 4.7/61.7 ± 2.3 mm Hg after standing for 1 min (22). Patient 40 also had abnormal responses to the cold pressor test, in which she showed a systolic blood pressure response of 7.22 ± 0.17 mm Hg and a diastolic blood pressure response of 7.42 ± 0.13 mm Hg after forearm immersion in ice-cold water for 1 min; likewise, this subject had abnormal responses to an orthostatic hypotension test (fall in blood pressure from 171.2 ± 3.5/108.7 ± 2.9 mm Hg to 143.2 ± 5.3/80.0 ± 4.08 mm Hg after standing for 1 min). Sympathetic system dysfunction was observed in the homozygous female child (patient 54), as assessed by a cold pressor response test, in which the patient showed a systolic blood pressure response of 7.57 ± 0.17 mm Hg and a diastolic blood pressure response of 7.05 ± 0.13 mm Hg after forearm immersion in ice-cold water for 1 min, and by an orthostatic hypotension test (fall in blood pressure from 113.7 ± 3.5/70.5 ± 4.2 mm Hg to 86.7 ± 2.21/62.7 ± 2.22 mm Hg after standing for 1 min). We have compared cold pressor response test results in patients with those in a control group of 15 age- and sex- matched healthy subjects (systolic cold pressor response, 10.6 ± 0.372; diastolic cold pressor response, 12.0 ± 0.377). There are significant difference in both systolic (z = -4.74; P < 0.001) and diastolic (z = -4.754; P < 0.001) cold pressure responses between the patients and the control group. Sympathetic function was normal in heterozygous and wild-type subjects.
Patient 47 had a basal aldosterone concentration of 25 pg/mL (normal, 30–355 pg/mL) and a renin concentration of 0.5 ng/mL (normal, 1.5–5.7 ng/mL). There were also virtually no aldosterone and renin responses to postural test (supine position: aldosterone, <10 pg/mL; renin, 0.3 ng/mL; upright position: aldosterone, <10 pg/mL; renin, 0.3 ng/mL). A postural test in patient 40 showed an adequate response of aldosterone and renin (supine position: aldosterone, 50.3 pg/mL; renin, 1.4 ng/mL; upright position: aldosterone, 92.3 pg/mL; renin, 4.5 ng/mL). A postural test in patient 23 showed an adequate response of aldosterone and renin (supine position: aldosterone, <25 pg/mL; renin, 0.3 ng/mL; upright position: aldosterone, 127.5 pg/mL; renin, 4.8 ng/mL).
As shown in Table 1, available data for body fat percent showed
that homozygous patients had a pronounced increase in body fat.
Moreover, body fat determination in four male and one female
heterozygous subjects demonstrated that three of four heterozygous
males and female heterozygous subjects also had increased body fat
(Tables 5 and 6).
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Discussion |
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As both ob/ob and db/db mice show stunted growth curves (28), our data indicate that the GH response to stimulation is disturbed in two homozygous adult patients, although we could not perform stimulation tests in another two homozygous patients. However, their heights are not less than those of heterozygous or wild-type relatives. Obese children and adults have a decrement in spontaneous GH secretion as well as a blunted response of GH to stimulation tests (29). Further studies are needed to characterize their patterns of GH secretion and to verify that poor stimulation was due to leptin deficiency rather than to obesity.
The obese are usually protected against osteoporosis and have increased BMD. This has been attributed to the mechanical effects of their excessive weight on bone tissue. Because only the male subject exhibited osteopenia, we suggest that the combined deficiency of leptin and testosterone may be particularly detrimental to bone function in this patient, as two adult female patients have normal BMD. These different observations of BMD between male and female patients suggest that factors other than leptin deficiency, such as sex steroids, affected BMD. Although recent in vitro studies demonstrated the effect of leptin on bone metabolism (30, 31), our recent observation in postmenopausal women with osteoporosis (32) and the findings of two other studies (33, 34) could not demonstrate a relation between plasma leptin levels and BMD. Regarding PTH values, we found elevated plasma PTH levels in two obese patients, in another subject it is in upper normal range, and in one subject it is in normal range. Plasma calcium values are low only in one obese patient. However, the levels of PTH have been reported to be increased in morbidly obese subjects (35, 36). Thus, further studies are needed to explain the role of leptin in bone and calcium metabolism. Nevertheless, the data presented here on alterations in BMD and plasma calcium in these obese, leptin-deficient subjects indicate that leptin may be a link between adipose tissue and bone and calcium metabolism, although the mechanism for such an effect remains to be elucidated.
The homozygous child in this family has subclinical hypothyroidism, and this may be due to a hypothalamic disturbance. Interestingly, Montaque et al. (14) reported two children who had an ob mutation and also had high TSH levels. However, it is not clear why in this family adult homozygous have normal thyroid function tests. Impairment of the hypothalamo-pituitary thyroid axis is not clearly demonstrated in ob/ob mice or Ob receptor-deficient rodents. However, it has been shown that leptin prevents the fasting-induced suppression of TRH expression in the rodent hypothalamus (37). We have recently demonstrated that plasma leptin concentrations are increased in hyperthyroidism and unchanged in hypothyroidism (38), although other studies did not demonstrate any alteration in plasma leptin levels in thyroid dysfunction (39, 40). All of these heterozygous patients have normal thyroid function tests. Those data suggest that leptin deficiency influences the hypothalamic-pituitary-thyroid axis at least in childhood by mechanisms that have not yet been identified, and that during adulthood, leptin-deficient subjects achieve normal thyroid function. One may also consider that the child had a primary thyroid defect unrelated to leptin deficiency. However, this child has a normal thyroid gland and negative thyroid antibodies. Moreover, three children reported to date to have Ob mutation have elevated TSH levels, suggesting that elevated TSH levels are more likely to be due to leptin deficiency. Evidence in support of this suggestion also comes from patients with leptin receptor mutation who had hypothalamic hypothyroidism (15).
Leptin concentrations are shown to be inversely related to ACTH and
cortisol and modulate the levels of endogenous cortisol (9). Although
two homozygous patients have elevated plasma cortisol and three have
elevated plasma ACTH levels, all of them have normal free urinary
cortisol levels and normal cortisol response to a 1-mg dexamethasone
suppression test. However, evaluation of diurnal variation in the three
adult homozygous patients suggests a disturbance of diurnal
rhythmicity. Further studies using frequent sampling methods are
needed to fully characterize hypothalamic-pituitary-adrenal function in
leptin-deficient subjects. Previous studies demonstrated that leptin
exerts a mild suppression of adrenal 17-hydroxylase enzyme in
humans. Therefore, it is interesting that we found low 17-OHP levels in
the three adult homozygous subjects who had very low concentrations of
a truncated leptin molecule, but not in the homozygous child. It is
possible that in the adult subjects, 17-OHP concentrations are low
secondary to anovulation.
Previous studies (41, 42) reported that leptin acts on the renal tubules to promote natriuresis and diuresis; therefore, we evaluated urine volume in homozygous patients. We could not find any abnormalities in urine volume in these leptin-deficient patients.
Despite their severe obesity, we observed that these leptin-deficient subjects exhibited only mildly elevated fasting triglycerides concentrations; however, their cholesterol, LDL-C, and VLDL levels were in the normal range, and their HDL-C levels were at the lower limit of the normal range.
Obesity is characterized by elevated plasma levels of leptin and fasting insulin and an exaggerated insulin response to an oral glucose load (43). As these obese, leptin-deficient subjects exhibit varying degrees of insulin resistance (fasting insulin of 30 or greater), we propose that leptin contributes to but is not required for the impairments in glucose homeostasis that occur in obesity.
In light of the impairments of sympathetic response observed in these patients, we predicted that they would have robust renin-aldosterone responses; however, contrary to expectation, one of three adult homozygous patient had impairment of renin-aldosterone function in a postural test. A recent study demonstrated that aldosterone is higher in obese subjects (44). However, we could not find elevated aldosterone levels in our obese subjects, indicating a possible disturbance of renin-aldosterone function. In light of our observation of impairment in a postural test in one of three homozygous patients, we believe that further studies are needed to clarify the relationship between leptin and renin-aldosterone function.
Our data indicate that leptin deficiency is associated with alterations in human immunity. It is known that ob/ob mice with leptin deficiency have reduced T cell function (45). Recently, Lord et al. (12) also documented that leptin promotes T cell activity in vitro. It should be noted that the obese phenotype of our leptin-deficient subjects is very distinct. First, in this large extended family of over 40 people there are no other obese or overweight individuals. Second, their obesity is characterized by normal weight at birth, followed by rapid and profound weight gain occurring in the context of a voracious appetite. For example, patient 47 was 4 kg at birth; his body weight doubled in the first 2 months of life. All of the seven deceased obese children had the same phenotype; therefore, it would be reasonable to assume that they were also leptin deficient. Considering the deaths of 7 of 11 obese children but no deaths in a total of 19 normal weight children in the youngest generation of this family, all raised in the same environment and with the same access to nutrients and the same medical services, we presume that the deaths of the obese children might have been due to leptin deficiency causing diminished immunity and increased susceptibility to infection or other diseases (46). Indeed, in this family, the odds ratio of death due to the obese phenotype is 25.4, indicating that this mutation severely impairs the ability to survive past childhood.
Heterozygosity of the leptin gene in rodents results in increased body fat mass in heterozygous animals relative to that in +/+ animals, but has no significant effect on body weight. Similarly, we found increased body fat in our heterozygous subjects, indicating that heterozygosity of the leptin gene in humans may also influence body fat mass.
As shown in Tables 4 and 5, patient 51 has a prepubertal range of FSH,
LH, and testosterone concentrations. It should be noted that he is now
12 yr old and has not yet entered puberty. Patient 21 has low renin but
normal aldosterone levels. That patient does not meet clinical or
laboratory criteria for a diagnosis of abnormal renin-aldosterone
function. Other heterozygous male and female subjects have normal renin
and aldosterone levels. As shown in Table 5, patients 34, 22, and 41
have anemia, and clinical and laboratory assessments demonstrated that
they have iron deficiency.
Our detailed clinical, laboratory, and radiological assessments of these patients provide a novel level of understanding of the role of leptin in human biology. It seems that leptin is crucial for survival, particularly in childhood. As there are no obese individuals in this family other than those who are homozygous for a missense leptin mutation, we presume that the 7 obese children who died in childhood and who had the same body mass phenotype also had the same mutation as these patients. Of the 11 obese children born in this family, only 4 survived. The youngest individual, who is 7 yr old, has abnormal thyroid function tests; in contrast, thyroid function is normal in all adult homozygous patients. Likewise, the 2 youngest adults are hypogonadic; however, the older adult entered puberty after a delay of over 20 yr. It thus appears that leptin is crucial for survival and adequate development; however, in those humans who survive despite leptin deficiency, over a time span of several decades other factors seem to bring back to normal functions such as thyroid axis activity, reproduction, and possibly immunity that were initially dysregulated in the absence of leptin. Due to the longevity of humans we could observe in these patients very gradual compensations of functions that were initially impaired due to a mutated leptin molecule. This type of insight over a life span of several decades could not have been gained from studies in animals with a much shorter life, such as the ob/ob mouse, which has a mutated stop codon in the leptin molecule that is in the same position as the mutation observed in this family. Although further studies are needed, we found evidence for novel potential actions of leptin in the regulation of 1) GH and PTH-calcium metabolism and BMD, and 2) renin-aldosterone function. These data also indicate that there may be several new pharmacological targets for leptin agonists and antagonists in the treatment of human disease.
Support for the hypothesis that the obese may have central, but not peripheral, resistance to the effects of leptin is provided by our findings 1) that in contrast to nonleptin-deficient obese individuals who are protected against osteoporosis, our leptin-deficient homozygous subjects had alterations in PTH-calcium and BMD; and 2) that in the context of severe obesity, patients with a mutated leptin molecule do not present with risk factors for cardiovascular disease, such as hypertension, impairments in lipid, or hyperglycemia that are commonly seen in the nonleptin-deficient obese. Future studies should test the hypothesis that hyperleptinemia mediates the cardiovascular morbidity that is associated with obesity.
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Acknowledgments |
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Received March 23, 1999.
Revised May 26, 1999.
Accepted June 17, 1999.
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 A. Silvani, S. Bastianini, C. Berteotti, C. Franzini, P. Lenzi, V. Lo Martire, and G. Zoccoli Sleep Modulates Hypertension in Leptin-Deficient Obese Mice Hypertension, February 1, 2009; 53(2): 251 - 255. [Abstract] [Full Text] [PDF]
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 G. R. Hajer, T. W. van Haeften, and F. L.J. Visseren Adipose tissue dysfunction in obesity, diabetes, and vascular diseases Eur. Heart J., December 2, 2008; 29(24): 2959 - 2971. [Abstract] [Full Text] [PDF]
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 D. A. Morgan, D. R. Thedens, R. Weiss, and K. Rahmouni Mechanisms mediating renal sympathetic activation to leptin in obesity Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2008; 295(6): R1730 - R1736. [Abstract] [Full Text] [PDF]
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G. Paz-Filho, K. Esposito, B. Hurwitz, A. Sharma, C. Dong, V. Andreev, T. Delibasi, H. Erol, A. Ayala, M.-L. Wong, et al. Changes in insulin sensitivity during leptin replacement therapy in leptin-deficient patients Am J Physiol Endocrinol Metab, December 1, 2008; 295(6): E1401 - E1408. [Abstract] [Full Text] [PDF]
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 S. Park, B. J. Bivona, Y. Feng, E. Lazartigues, and L. M. Harrison-Bernard Intact renal afferent arteriolar autoregulatory responsiveness in db/db mice Am J Physiol Renal Physiol, November 1, 2008; 295(5): F1504 - F1511. [Abstract] [Full Text] [PDF]
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 S. S. Martin, A. Qasim, and M. P. Reilly Leptin Resistance: A Possible Interface of Inflammation and Metabolism in Obesity-Related Cardiovascular Disease J. Am. Coll. Cardiol., October 7, 2008; 52(15): 1201 - 1210. [Abstract] [Full Text] [PDF]
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 G. Matarese, C. Procaccini, and V. De Rosa The intricate interface between immune and metabolic regulation: a role for leptin in the pathogenesis of multiple sclerosis? J. Leukoc. Biol., October 1, 2008; 84(4): 893 - 899. [Abstract] [Full Text] [PDF]
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N. J. MacIver, S. R. Jacobs, H. L. Wieman, J. A. Wofford, J. L. Coloff, and J. C. Rathmell Glucose metabolism in lymphocytes is a regulated process with significant effects on immune cell function and survival J. Leukoc. Biol., October 1, 2008; 84(4): 949 - 957. [Abstract] [Full Text] [PDF]
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 J. L. Chan, C. J. Williams, P. Raciti, J. Blakeman, T. Kelesidis, I. Kelesidis, M. L. Johnson, M. O. Thorner, and C. S. Mantzoros Leptin Does Not Mediate Short-Term Fasting-Induced Changes in Growth Hormone Pulsatility but Increases IGF-I in Leptin Deficiency States J. Clin. Endocrinol. Metab., July 1, 2008; 93(7): 2819 - 2827. [Abstract] [Full Text] [PDF]
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 V. E F Crowley Overview of human obesity and central mechanisms regulating energy homeostasis Ann Clin Biochem, May 1, 2008; 45(3): 245 - 255. [Abstract] [Full Text] [PDF]
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 P. Kumpers, R. Horn, G. Brabant, A. Woywodt, M. Schiffer, H. Haller, and M. Haubitz Serum leptin and ghrelin correlate with disease activity in ANCA-associated vasculitis Rheumatology, April 1, 2008; 47(4): 484 - 487. [Abstract] [Full Text] [PDF]
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 K. Baicy, E. D. London, J. Monterosso, M.-L. Wong, T. Delibasi, A. Sharma, and J. Licinio From the Cover: Leptin replacement alters brain response to food cues in genetically leptin-deficient adults PNAS, November 13, 2007; 104(46): 18276 - 18279. [Abstract] [Full Text] [PDF]
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 M. S. Desruisseaux, Nagajyothi, M. E. Trujillo, H. B. Tanowitz, and P. E. Scherer Adipocyte, Adipose Tissue, and Infectious Disease Infect. Immun., March 1, 2007; 75(3): 1066 - 1078. [Full Text] [PDF]
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 I. S. Farooqi, T. Wangensteen, S. Collins, W. Kimber, G. Matarese, J. M. Keogh, E. Lank, B. Bottomley, J. Lopez-Fernandez, I. Ferraz-Amaro, et al. Clinical and Molecular Genetic Spectrum of Congenital Deficiency of the Leptin Receptor N. Engl. J. Med., January 18, 2007; 356(3): 237 - 247. [Abstract] [Full Text] [PDF]
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 I. S. Farooqi and S. O'Rahilly Genetics of Obesity in Humans Endocr. Rev., December 1, 2006; 27(7): 710 - 718. [Abstract] [Full Text] [PDF]
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 N. Stefanou, M. Satra, V. Papanikolaou, F. Kalala, N. Gatselis, A. Germenis, G. N. Dalekos, and A. Tsezou Leptin receptor isoforms mRNA expression in peripheral blood mononuclear cells from patients with chronic viral hepatitis. Experimental Biology and Medicine, November 1, 2006; 231(10): 1653 - 1663. [Abstract] [Full Text] [PDF]
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 G. Palmer, M. Aurrand-Lions, E. Contassot, D. Talabot-Ayer, D. Ducrest-Gay, C. Vesin, V. Chobaz-Peclat, N. Busso, and C. Gabay Indirect Effects of Leptin Receptor Deficiency on Lymphocyte Populations and Immune Response in db/db Mice. J. Immunol., September 1, 2006; 177(5): 2899 - 2907. [Abstract] [Full Text] [PDF]
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M. Otero, R. Lago, R. Gomez, C. Dieguez, F. Lago, J. Gomez-Reino, and O. Gualillo Towards a pro-inflammatory and immunomodulatory emerging role of leptin Rheumatology, August 1, 2006; 45(8): 944 - 950. [Abstract] [Full Text] [PDF]
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 S. O'Rahilly and I.S. Farooqi Genetics of obesity Phil Trans R Soc B, July 29, 2006; 361(1471): 1095 - 1105. [Abstract] [Full Text] [PDF]
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J. L. Chan, G. Matarese, G. K. Shetty, P. Raciti, I. Kelesidis, D. Aufiero, V. De Rosa, F. Perna, S. Fontana, and C. S. Mantzoros Differential regulation of metabolic, neuroendocrine, and immune function by leptin in humans PNAS, May 30, 2006; 103(22): 8481 - 8486. [Abstract] [Full Text] [PDF]
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E. A. Oral, E. D. Javor, L. Ding, G. Uzel, E. K. Cochran, J. R. Young, A. M. DePaoli, S. M. Holland, and P. Gorden Leptin Replacement Therapy Modulates Circulating Lymphocyte Subsets and Cytokine Responsiveness in Severe Lipodystrophy J. Clin. Endocrinol. Metab., February 1, 2006; 91(2): 621 - 628. [Abstract] [Full Text] [PDF]
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 C. W. Wieland, S. Florquin, E. D. Chan, J. C. Leemans, S. Weijer, A. Verbon, G. Fantuzzi, and T. van der Poll Pulmonary Mycobacterium tuberculosis infection in leptin-deficient ob/ob mice Int. Immunol., November 1, 2005; 17(11): 1399 - 1408. [Abstract] [Full Text] [PDF]
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 A. Bruno, P. Chanez, G. Chiappara, L. Siena, S. Giammanco, M. Gjomarkaj, G. Bonsignore, J. Bousquet, and A. M. Vignola Does leptin play a cytokine-like role within the airways of COPD patients? Eur. Respir. J., September 1, 2005; 26(3): 398 - 405. [Abstract] [Full Text] [PDF]
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 C Popa, M G Netea, T R D S Radstake, P L van Riel, P Barrera, and J W M van der Meer Markers of inflammation are negatively correlated with serum leptin in rheumatoid arthritis Ann Rheum Dis, August 1, 2005; 64(8): 1195 - 1198. [Abstract] [Full Text] [PDF]
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L. S. Tallam, D. E. Stec, M. A. Willis, A. A. da Silva, and J. E. Hall Melanocortin-4 Receptor-Deficient Mice Are Not Hypertensive or Salt-Sensitive Despite Obesity, Hyperinsulinemia, and Hyperleptinemia Hypertension, August 1, 2005; 46(2): 326 - 332. [Abstract] [Full Text] [PDF]
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 M. Banning Obesity: pathophysiology and treatment Perspectives in Public Health, July 1, 2005; 125(4): 163 - 167. [Abstract] [PDF]
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B. Mattioli, E. Straface, M. G. Quaranta, L. Giordani, and M. Viora Leptin Promotes Differentiation and Survival of Human Dendritic Cells and Licenses Them for Th1 Priming J. Immunol., June 1, 2005; 174(11): 6820 - 6828. [Abstract] [Full Text] [PDF]
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M. M. Grumbach A Window of Opportunity: The Diagnosis of Gonadotropin Deficiency in the Male Infant J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 3122 - 3127. [Abstract] [Full Text] [PDF]
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G. Matarese, S. Moschos, and C. S. Mantzoros Leptin in Immunology J. Immunol., March 15, 2005; 174(6): 3137 - 3142. [Abstract] [Full Text] [PDF]
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J. L. Chan, S. J. Moschos, J. Bullen, K. Heist, X. Li, Y.-B. Kim, B. B. Kahn, and C. S. Mantzoros Recombinant Methionyl Human Leptin Administration Activates Signal Transducer and Activator of Transcription 3 Signaling in Peripheral Blood Mononuclear Cells in Vivo and Regulates Soluble Tumor Necrosis Factor-{alpha} Receptor Levels in Humans with Relative Leptin Deficiency J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1625 - 1631. [Abstract] [Full Text] [PDF]
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M. Cote, P. Mauriege, J. Bergeron, N. Almeras, A. Tremblay, I. Lemieux, and J.-P. Despres Adiponectinemia in Visceral Obesity: Impact on Glucose Tolerance and Plasma Lipoprotein and Lipid Levels in Men J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1434 - 1439. [Abstract] [Full Text] [PDF]
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W. T. Gibson, I. S. Farooqi, M. Moreau, A. M. DePaoli, E. Lawrence, S. O'Rahilly, and R. A. Trussell Congenital Leptin Deficiency Due to Homozygosity for the {Delta}133G Mutation: Report of Another Case and Evaluation of Response to Four Years of Leptin Therapy J. Clin. Endocrinol. Metab., October 1, 2004; 89(10): 4821 - 4826. [Abstract] [Full Text] [PDF]
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 S. Bluher and C. S. Mantzoros The Role of Leptin in Regulating Neuroendocrine Function in Humans J. Nutr., September 1, 2004; 134(9): 2469S - 2474S. [Abstract] [Full Text] [PDF]
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S. Ten and N. Maclaren Insulin Resistance Syndrome in Children J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 2526 - 2539. [Abstract] [Full Text] [PDF]
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J. Licinio, S. Caglayan, M. Ozata, B. O. Yildiz, P. B. de Miranda, F. O'Kirwan, R. Whitby, L. Liang, P. Cohen, S. Bhasin, et al. Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults PNAS, March 30, 2004; 101(13): 4531 - 4536. [Abstract] [Full Text] [PDF]
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 D. V. Tortoriello, J. McMinn, and S. C. Chua Dietary-Induced Obesity and Hypothalamic Infertility in Female DBA/2J Mice Endocrinology, March 1, 2004; 145(3): 1238 - 1247. [Abstract] [Full Text] [PDF]
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H. Zarkesh-Esfahani, A. G. Pockley, Z. Wu, P. G. Hellewell, A. P. Weetman, and R. J. M. Ross Leptin Indirectly Activates Human Neutrophils via Induction of TNF-{alpha} J. Immunol., February 1, 2004; 172(3): 1809 - 1814. [Abstract] [Full Text] [PDF]
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M.-L. Wong, J. Licinio, B. O. Yildiz, C. S. Mantzoros, P. Prolo, M. Kling, and P. W. Gold Simultaneous and Continuous 24-Hour Plasma and Cerebrospinal Fluid Leptin Measurements: Dissociation of Concentrations in Central and Peripheral Compartments J. Clin. Endocrinol. Metab., January 1, 2004; 89(1): 258 - 265. [Abstract] [Full Text] [PDF]
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 I.S. Farooqi and S. O'Rahilly Monogenic Human Obesity Syndromes Recent Prog. Horm. Res., January 1, 2004; 59(1): 409 - 424. [Abstract] [Full Text]
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 T. M. Plant and M. L. Barker-Gibb Neurobiological mechanisms of puberty in higher primates Hum. Reprod. Update, January 1, 2004; 10(1): 67 - 77. [Abstract] [Full Text] [PDF]
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G. R. Steinberg, A. C. Smith, S. Wormald, P. Malenfant, C. Collier, and D. J. Dyck Endurance training partially reverses dietary-induced leptin resistance in rodent skeletal muscle Am J Physiol Endocrinol Metab, January 1, 2004; 286(1): E57 - E63. [Abstract] [Full Text] [PDF]
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 A. Ghazali, F. Grados, R. Oprisiu, D. Bunea, P. Moriniere, N. El Esper, I. El Esper, M. Brazier, J. C. Souberbielle, A. Fournier, et al. Bone mineral density directly correlates with elevated serum leptin in haemodialysis patients Nephrol. Dial. Transplant., September 1, 2003; 18(9): 1882 - 1890. [Abstract] [Full Text] [PDF]
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S. O'Rahilly, I. S. Farooqi, G. S. H. Yeo, and B. G. Challis Minireview: Human Obesity--Lessons from Monogenic Disorders Endocrinology, September 1, 2003; 144(9): 3757 - 3764. [Abstract] [Full Text] [PDF]
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C. J Hukshorn, M. S Westerterp-Plantenga, and W. H. Saris Pegylated human recombinant leptin (PEG-OB) causes additional weight loss in severely energy-restricted, overweight men Am. J. Clinical Nutrition, April 1, 2003; 77(4): 771 - 776. [Abstract] [Full Text] [PDF]
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M. Ozata, C. Dieguez, and F. F. Casanueva The Inhibition of Growth Hormone Secretion Presented in Obesity Is Not Mediated by the High Leptin Levels: A Study in Human Leptin Deficiency Patients J. Clin. Endocrinol. Metab., January 1, 2003; 88(1): 312 - 316. [Abstract] [Full Text] [PDF]
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 M Labib The investigation and management of obesity J. Clin. Pathol., January 1, 2003; 56(1): 17 - 25. [Abstract] [Full Text] [PDF]
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M. L. Barker-Gibb, A. Sahu, C. R. Pohl, and T. M. Plant Elevating Circulating Leptin in Prepubertal Male Rhesus Monkeys (Macaca mulatta) Does Not Elicit Precocious Gonadotropin-Releasing Hormone Release, Assessed Indirectly J. Clin. Endocrinol. Metab., November 1, 2002; 87(11): 4976 - 4983. [Abstract] [Full Text] [PDF]
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G. Kilciler, M. Ozata, C. Oktenli, S.Y. Sanisoglu, E. Bolu, N. Bingol, M. Kilciler, I. C. Ozdemir, and M. Kutlu Diurnal Leptin Secretion Is Intact in Male Hypogonadotropic Hypogonadism and Is Not Influenced by Exogenous Gonadotropins J. Clin. Endocrinol. Metab., November 1, 2002; 87(11): 5023 - 5029. [Abstract] [Full Text] [PDF]
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 S E Moore, G Morgan, A C Collinson, J A Swain, M A O'Connell, and A M Prentice Leptin, malnutrition, and immune response in rural Gambian children Arch. Dis. Child., September 1, 2002; 87(3): 192 - 197. [Abstract] [Full Text] [PDF]
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G. M. Lord, G. Matarese, J. K. Howard, S. R. Bloom, and R. I. Lechler Leptin inhibits the anti-CD3-driven proliferation of peripheral blood T cells but enhances the production of proinflammatory cytokines J. Leukoc. Biol., August 1, 2002; 72(2): 330 - 338. [Abstract] [Full Text] [PDF]
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A. Garg and A. Misra Hepatic Steatosis, Insulin Resistance, and Adipose Tissue Disorders J. Clin. Endocrinol. Metab., July 1, 2002; 87(7): 3019 - 3022. [Full Text] [PDF]
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C. Grunfeld Leptin and the Immunosuppression of Malnutrition J. Clin. Endocrinol. Metab., July 1, 2002; 87(7): 3038 - 3039. [Full Text] [PDF]
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E. A. Oral, E. Ruiz, A. Andewelt, N. Sebring, A. J. Wagner, A. M. Depaoli, and P. Gorden Effect of Leptin Replacement on Pituitary Hormone Regulation in Patients with Severe Lipodystrophy J. Clin. Endocrinol. Metab., July 1, 2002; 87(7): 3110 - 3117. [Abstract] [Full Text] [PDF]
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H. Blain, A. Vuillemin, F. Guillemin, R. Durant, B. Hanesse, N. de Talance, B. Doucet, and C. Jeandel Serum Leptin Level Is a Predictor of Bone Mineral Density in Postmenopausal Women J. Clin. Endocrinol. Metab., March 1, 2002; 87(3): 1030 - 1035. [Abstract] [Full Text] [PDF]
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M. Ozata, C. Oktenli, M. Gulec, T. Ozgurtas, F. Bulucu, K. Caglar, N. Bingol, A. Vural, and I. C. Ozdemir Increased Fasting Plasma Acylation-Stimulating Protein Concentrations in Nephrotic Syndrome J. Clin. Endocrinol. Metab., February 1, 2002; 87(2): 853 - 858. [Abstract] [Full Text] [PDF]
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M. Ozata Different Presentation of Bone Mass in Mice and Humans with Congenital Leptin Deficiency J. Clin. Endocrinol. Metab., February 1, 2002; 87(2): 951 - 951. [Full Text]
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N. Busso, A. So, V. Chobaz-Peclat, C. Morard, E. Martinez-Soria, D. Talabot-Ayer, and C. Gabay Leptin Signaling Deficiency Impairs Humoral and Cellular Immune Responses and Attenuates Experimental Arthritis J. Immunol., January 15, 2002; 168(2): 875 - 882. [Abstract] [Full Text] [PDF]
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 R. FAGGIONI, K. R. FEINGOLD, and C. GRUNFELD Leptin regulation of the immune response and the immunodeficiency of malnutrition FASEB J, December 1, 2001; 15(14): 2565 - 2571. [Abstract] [Full Text] [PDF]
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G. FRUHBECK and J. GOMEZ-AMBROSI Rationale for the existence of additional adipostatic hormones FASEB J, September 1, 2001; 15(11): 1996 - 2006. [Abstract] [Full Text] [PDF]
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M. L.G. Correia, D. A. Morgan, J. L. Mitchell, W. I. Sivitz, A. L. Mark, and W. G. Haynes Role of Corticotrophin-Releasing Factor in Effects of Leptin on Sympathetic Nerve Activity and Arterial Pressure Hypertension, September 1, 2001; 38(3): 384 - 388. [Abstract] [Full Text] [PDF]
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M. Ozata, D. Gungor, M. Turan, G. Ozisik, N. Bingol, T. Ozgurtas, and I. C. Ozdemir Improved Glycemic Control Increases Fasting Plasma Acylation-Stimulating Protein and Decreases Leptin Concentrations in Type II Diabetic Subjects J. Clin. Endocrinol. Metab., August 1, 2001; 86(8): 3659 - 3664. [Abstract] [Full Text] [PDF]
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W.-S. Yang, W.-J. Lee, T. Funahashi, S. Tanaka, Y. Matsuzawa, C.-L. Chao, C.-L. Chen, T.-Y. Tai, and L.-M. Chuang Weight Reduction Increases Plasma Levels of an Adipose-Derived Anti-Inflammatory Protein, Adiponectin J. Clin. Endocrinol. Metab., August 1, 2001; 86(8): 3815 - 3819. [Abstract] [Full Text] [PDF]
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B. Burguera, L. C. Hofbauer, T. Thomas, F. Gori, G. L. Evans, S. Khosla, B. L. Riggs, and R. T. Turner Leptin Reduces Ovariectomy-Induced Bone Loss in Rats Endocrinology, August 1, 2001; 142(8): 3546 - 3553. [Abstract] [Full Text] [PDF]
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C. S. Mantzoros, M. Ozata, A. B. Negrao, M. A. Suchard, M. Ziotopoulou, S. Caglayan, R. M. Elashoff, R. J. Cogswell, P. Negro, V. Liberty, et al. Synchronicity of Frequently Sampled Thyrotropin (TSH) and Leptin Concentrations in Healthy Adults and Leptin-Deficient Subjects: Evidence for Possible Partial TSH Regulation by Leptin in Humans J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 3284 - 3291. [Abstract] [Full Text] [PDF]
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 A. Sonmez, U. Kisa, G. Uckaya, T. Eyileten, B. Comert, B. Koc, F. Kocabalkan, and M. Ozata Effects of losartan treatment on T-cell activities and plasma leptin concentrations in primary hypertension Journal of Renin-Angiotensin-Aldosterone System, June 1, 2001; 2(2): 112 - 116. [Abstract] [PDF]
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L. Ghizzoni, G. Mastorakos, M. Ziveri, M. Furlini, A. Solazzi, A. Vottero, and S. Bernasconi Interactions of Leptin and Thyrotropin 24-Hour Secretory Profiles in Short Normal Children J. Clin. Endocrinol. Metab., May 1, 2001; 86(5): 2065 - 2072. [Abstract] [Full Text]
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G. Fantuzzi and R. Faggioni Leptin in the regulation of immunity, inflammation, and hematopoiesis J. Leukoc. Biol., October 1, 2000; 68(4): 437 - 446. [Abstract] [Full Text]
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A. M. Rice, J. N. Fain, and S. A. Rivkees A1 Adenosine Receptor Activation Increases Adipocyte Leptin Secretion Endocrinology, April 1, 2000; 141(4): 1442 - 1445. [Abstract] [Full Text] [PDF]
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