Metabolic Abnormalities and the Role of Leptin in Human Obesity

F-Xavier Pi-Sunyer and Blandine Laferrère

Obesity Research Center Columbia University College of Physicians and Surgeons New York, New York 10025


    Introduction
 Top
 Introduction
 Background
 Regulation of leptin production
 Energy intake
 Fat distribution and leptin
 Insulin
 Glucocorticoids
 Hypertension
 Dyslipidemia
 Energy expenditure
 Summary
 References
 
OBESITY is the most common nutritional disease in the United States, affecting about one fourth of the population (1). It leads to increased morbidity and mortality and is associated with insulin resistance, dyslipidemia, diabetes mellitus, hypertension, and cardiovascular disease (2). The morbidity and mortality is increased in persons with abdominal or upper body fat distribution independent of the obesity itself (2, 3, 4, 5, 6, 7, 8).

The treatment of obesity, even using comprehensive multidisciplinary approaches, including drugs, is very difficult, with patients generally losing 10 to 15% of their baseline obese body weight at the most, plateauing after 4–6 months of weight loss effort, then beginning to regain. A better understanding of the etiology and pathophysiology of obesity is necessary in order to develop more effective prevention and treatment measures.

The discovery of leptin (9) and its receptor (10) opened a new era in obesity research and brought some hope to the obesity community. Although leptin appears to be a key protein in energy balance in rodents, its physiological role in humans is not fully known, and the mechanism by which its secretion is regulated in humans is not clear. Thus far, the role of leptin in metabolic abnormalities associated with human obesity has not been studied extensively, although some data suggest that hyperleptinemia could relate to the metabolic syndrome.


    Background
 Top
 Introduction
 Background
 Regulation of leptin production
 Energy intake
 Fat distribution and leptin
 Insulin
 Glucocorticoids
 Hypertension
 Dyslipidemia
 Energy expenditure
 Summary
 References
 
Leptin, encoded by the ob gene (9) is a 167-amino acid protein produced and released exclusively by adipose cells (for review see 11). It circulates in the blood mostly bound to a family of proteins (12, 13). Crossing the blood-brain barrier (14) into the central nervous system, it acts at the level of the hypothalamus by binding to its receptor and activating secondary signals that inhibit food intake and increase energy expenditure (15). When leptin is given to leptin deficient ob/ob mice, which have a mutation in the ob gene and do not make leptin, the obesity and metabolic abnormalities present in these mice are corrected. An increase in energy expenditure, a decrease in food intake, and a decrease in plasma glucose, insulin, and cortisol levels (16, 17, 18) occur. Leptin injected into wild-type mice also leads to weight loss (15, 16, 17, 18, 19, 20) and prevents the decrease in energy expenditure usually seen with weight loss (18). The db/db mouse and the fa/fa rat do not respond to leptin because they have an abnormal leptin receptor (21). Hypothalamic brain lesions cause leptin ineffectiveness, supporting the thesis that leptin acts in the hypothalamus to regulate food intake and thermogenesis (22).

The leptin receptor was cloned from mouse choroid plexus (10) and has been found in the cytokine family of receptors. At least five alternatively spliced forms of the receptor have been found (23). One of these, Ob-Rb, is heavily expressed in the hypothalamus and less so elsewhere (23, 24). This receptor has been found to be abnormal in db/db mice (23, 25). How the leptin receptor is activated and what its subsequent signaling is have not yet been elucidated. But it is known that the arcuate, the ventromedial, and lateral hypothalamic nuclei are principal brain sites for Ob-Rb expression (26, 27, 28).

The receptor may respond differently to the high levels of leptin secreted by a high fat mass and the low levels of leptin produced by starvation. High leptin seems to inhibit neuropeptide Y messenger RNA (mRNA) expression and thus shut off activity of this powerful stimulator of food intake (29). It has also been shown that inhibition of binding of MSH to the melanocortin receptor (MC4R) may be involved. With hypocaloric dieting, leptin levels fall (30). This results in highly expressed neuropeptide Y in the hypothalamus, leading to increased food intake. Corticotropin releasing hormone (CRH) may also be involved (31).

None of the normalizing metabolic effects that occur with the provision of leptin to ob/ob mice have been shown in obese humans so far. However, a long-acting modified ob protein caused a dose-dependent suppression of spontaneous food intake in rhesus monkeys (32). The pharmaceutical company Amgen, in a press release, has stated that injected leptin had some effect on lowering body weight in obese volunteers but did not give quantitative details about the weight loss or about other metabolic effects (33).

In humans, leptin is secreted into the circulation in a pulsatile mode (32 pulses in 24 h, with each pulse duration being about 33 min, an interpeak interval of 43 min and a pulse height showing a 132% increase over the preceding baseline). It follows a circadian rhythm, peaking at night (34). Serum leptin levels are higher in women than in men. The regulation of serum leptin levels in humans is not well understood. The levels increase as body fat mass increases (35, 36). Obese individuals have very high levels, so they must be resistant to the action of leptin on inhibition of food intake and increase in energy expenditure. To see if obesity could be related to an abnormality of leptin production, human ob gene mutations have been sought. Thus far, only two mutations have been found; one is a mutation in the coding sequence of the leptin gene in two members of a family in the United Kingdom (37), and the other is a mutation of the leptin-receptor gene in members of a family in France (38). Many other obese patients have been studied with no such success (39). Thus, human obesity is not due primarily to a lack of production of leptin or the production of an abnormal leptin. Also, there is no evidence that obesity in humans is due to the presence of abnormal leptin receptors (40). Thus, if there is a defect in the leptin pathway in human obesity, it could be due either to an inability of the leptin to appropriately enter the central nervous system or to a post-receptor defect in the subsequent leptin signaling cascade. It is likely that the transmission of the signal will involve many other molecules in the central nervous system. Particularly prominent studies have focused on neuropeptide Y and the proopiomelanocortin (POMC) (MSH precursor) pathway (41). Leptin could inhibit NPY, a peptide that is stimulatory to feeding, or it could enhance the binding of MSH to the MC4 receptor, thereby inhibiting food intake (42). But other neurotransmitters may also be involved.


    Regulation of leptin production
 Top
 Introduction
 Background
 Regulation of leptin production
 Energy intake
 Fat distribution and leptin
 Insulin
 Glucocorticoids
 Hypertension
 Dyslipidemia
 Energy expenditure
 Summary
 References
 
It is clear, however, that other regulatory factors besides fat mass are involved in the secretion of leptin. At each level of fat mass, leptin levels are quite variable from one individual to another (43). Also, serum leptin levels can change independently of fat mass, for example during fasting (44). At least two hormones have been implicated in modulating serum leptin levels: insulin and glucocorticoids. Both of these hormones are also implicated in the "metabolic syndrome" (4). Low leptin levels have been reported to predict weight gain in Pima Indians (45), suggesting that chronic under-secretion could be a cause of obesity.


    Energy intake
 Top
 Introduction
 Background
 Regulation of leptin production
 Energy intake
 Fat distribution and leptin
 Insulin
 Glucocorticoids
 Hypertension
 Dyslipidemia
 Energy expenditure
 Summary
 References
 
Plasma levels of leptin change with a change in energy intake. Fasting induces a rapid decrease of leptin levels, but this can be prevented if glucose and insulin are maintained at basal levels (44). Administration of glucose after a prolonged fast induces an acute increase in serum leptin levels in humans (46). Daytime feeding does not produce any acute change of leptin in humans but may be responsible for the nocturnal leptin surge that is prevented by a prolonged fast (44, 46). Leptin increases between 5 and 10 h after massive short-term overfeeding (47). The increase in leptin levels from nadir to peak is related to insulin excursions in response to meals (48), and shifting meal time by 6.5 h without changing the light and sleep cycles will shift plasma leptin rhythm by 5–7 hours (49).


    Fat distribution and leptin
 Top
 Introduction
 Background
 Regulation of leptin production
 Energy intake
 Fat distribution and leptin
 Insulin
 Glucocorticoids
 Hypertension
 Dyslipidemia
 Energy expenditure
 Summary
 References
 
Although the metabolic disturbances linked to obesity relate closely to fat distribution, leptin secretion does not appear to be affected by abdominal obesity. In human obesity, serum leptin levels are correlated best to fat mass and to percent body fat, with a higher expression of the ob gene in adipose tissue of severely obese compared with lean individuals (43). This ob gene expression is related to total body fatness (50) and to subcutaneous adiposity (51), but not to intra-abdominal fat (52, 53).

The level of expression of leptin mRNA varies from one adipose tissue depot to another, with some differences among reports. While one group of investigators has found increased expression of ob mRNA in omental fat cells from massively obese humans (54), most have found a higher level of expression in subcutaneous as compared with intra-abdominal adipose tissue (52, 53).

Further investigation is needed of leptin secretion in relation to fat distribution and the differing biological functions of the subcutaneous and intra-abdominal depots in this regard. In addition, two problems remain. First, many of the metabolic abnormalities linked to obesity are related to body fat distribution, especially intra-abdominal fat. Yet except for one report (55), other studies have not shown any correlation between intra-abdominal fat and leptin levels. According to Lonnqvist (56), only 40% of leptin variability can be explained by fat mass. The other factors responsible for the variability of leptin at each level of fat mass are unknown.


    Insulin
 Top
 Introduction
 Background
 Regulation of leptin production
 Energy intake
 Fat distribution and leptin
 Insulin
 Glucocorticoids
 Hypertension
 Dyslipidemia
 Energy expenditure
 Summary
 References
 
Animal data have documented that ob mRNA is up- or down-regulated by a rise or fall in insulin levels. Longitudinal study of the development of obesity in fa/fa rats shows a parallel increase in white adipose tissue ob mRNA levels and plasma insulin levels. However, in adult obese rats, ob mRNA does not respond to insulin (57).

In humans, there is some evidence suggesting a potential role for insulin in leptin regulation. Serum leptin correlates with fasting insulin levels (50, 58, 59), and a few studies have found a positive relationship between insulin resistance and hyperleptinemia (60, 61).

Insulin has a stimulatory effect on serum leptin after 6 h at high physiological concentration (62) and at supraphysiological concentration (63) or when given for a prolonged period of time during an hyperinsulinemic hyperglycemic clamp (64). A recent study showed that physiological levels of insulinemia can increase plasma leptin in a dose-dependent manner (65). One study has reported that the increase in leptin levels from nadir to peak is related to insulin excursions in response to meals (48).

However, in humans, most studies have been unable to detect an effect of insulin on leptin, and the increase in plasma insulin secondary to feeding does not increase serum leptin (58, 59, 66, 67, 68). The presence of diabetes does not affect leptin (60), and diabetes does not alter the relationship of leptin and body mass index. Leptin levels are not different between diabetic and nondiabetic subjects (69).

Because ob/ob mice develop insulin resistance in the absence of leptin, it is unlikely that leptin is a major factor responsible for the induction of insulin resistance in obesity. Nevertheless, some recent reports indicate that leptin could be a mechanism by which increased adiposity increases insulin resistance (70). Leptin antagonizes insulin signaling in hepatoma cells, decreasing insulin-induced tyrosine phosphorylation of IRS-1, a step leading to many of the metabolic actions of insulin (glucose transport, kinase pathway). Leptin also antagonizes the ability of insulin to decrease mRNA encoding PEPCK, the enzyme catalyzing the rate-limiting step in gluconeogenesis. However, many unanswered questions remain about how leptin might affect insulin action (71). There is no effect of in vitro leptin on glucose transport in muscle or adipocytes (72).


    Glucocorticoids
 Top
 Introduction
 Background
 Regulation of leptin production
 Energy intake
 Fat distribution and leptin
 Insulin
 Glucocorticoids
 Hypertension
 Dyslipidemia
 Energy expenditure
 Summary
 References
 
The permissive role of glucocorticoid hormones in the genesis and maintenance of obesity is well demonstrated in animal models (73, 74). Human obesity is associated with a relative hypercortisolism, especially in central or upper body obesity (75, 76, 77, 78, 79, 80). The hypercortisolism of Cushing’s disease is associated with obesity. Both of these hypercortisolemic states are associated with hyperleptinemia (81). Also, oral administration of glucocorticoid has been shown to increase human leptin plasma levels (82, 83, 84, 85, 86) as well as leptin mRNA in adipose tissue in vivo (85). It has recently been shown that glucocorticoids inhibit the action of central leptin (87) in rodents. It is possible, therefore, that the relative hypercortisolism of obesity could generate glucocorticoid-induced leptin resistance and play a role in the pathogenesis of obesity (87).


    Hypertension
 Top
 Introduction
 Background
 Regulation of leptin production
 Energy intake
 Fat distribution and leptin
 Insulin
 Glucocorticoids
 Hypertension
 Dyslipidemia
 Energy expenditure
 Summary
 References
 
Some animal data suggest that leptin may have actions influencing the autonomic cardiovascular system, with sympathoexcitatory action. However, acute leptin administration does not increase arterial blood pressure or heart rate (88). In humans, leptin levels show a positive correlation with mean arterial, systolic, and diastolic blood pressure in men but not in women (60) and a positive correlation with mean blood pressure (89). Potential mechanisms of action, if there is a direct causal effect, need to be explored.


    Dyslipidemia
 Top
 Introduction
 Background
 Regulation of leptin production
 Energy intake
 Fat distribution and leptin
 Insulin
 Glucocorticoids
 Hypertension
 Dyslipidemia
 Energy expenditure
 Summary
 References
 
The relationship between leptin and circulating lipid particles does not seem strong. One study found no relation between leptin and lipids or lipoproteins (90). A correlation was found between leptin, triglycerides, HDL-cholesterol (89) or HDL-C, and apo B (91), but the association lost its significance after adjustment for fat mass in both studies. A positive association has been reported between leptin and two measures of HDL, HDL-TG and HDL-apo A-1, but not with HDL-C (92).


    Energy expenditure
 Top
 Introduction
 Background
 Regulation of leptin production
 Energy intake
 Fat distribution and leptin
 Insulin
 Glucocorticoids
 Hypertension
 Dyslipidemia
 Energy expenditure
 Summary
 References
 
In contrast to rodents, no relationship has been found between leptin and energy expenditure in humans (60). This lack of correlation between changes in leptin and changes in energy expenditure suggest that leptin is not the primary signal that mediates the changes of energy expenditure that accompany altered body weight in humans (36). Leptin has had an effect on the expression of UCP3 mRNA in brown adipose tissue and muscle (93). Future research will bring new insight on the role of leptin in energy balance.


    Summary
 Top
 Introduction
 Background
 Regulation of leptin production
 Energy intake
 Fat distribution and leptin
 Insulin
 Glucocorticoids
 Hypertension
 Dyslipidemia
 Energy expenditure
 Summary
 References
 
While the hyperleptinemia of obesity is likely to be associated with the metabolic complications of obesity/hyperinsulinemia/insulin resistance, it is not associated with diabetes, with the relative hypercortisolism of upper body obesity, with hypertension in women, (it is in men), or with dyslipidemia. Overall, the correlations between leptin and the metabolic diseases associated with obesity are weak. The equivocal results of an association of leptin with components of the metabolic syndrome make it unlikely that leptin affects these directly. (On the other hand, these correlations, when found, preclude any causal relationship between leptin and metabolic diseases.) There are experimental data showing a definite role for insulin and glucocorticoids in the regulation of leptin, and of leptin in the regulation of insulin. More data are required on the effects of leptin, but it is likely that leptin will not be a major link between obesity and the metabolic syndrome. Certainly, however, when leptin is available for clinical use, its effect on different aspects of the metabolic syndrome will be worth studying.


    References
 Top
 Introduction
 Background
 Regulation of leptin production
 Energy intake
 Fat distribution and leptin
 Insulin
 Glucocorticoids
 Hypertension
 Dyslipidemia
 Energy expenditure
 Summary
 References
 

  1. Kuczmarski R, Flegal K, Campbell S, Johnson C. 1994 Increasing prevalence of overweight among US adults. The National Health and Nutrition Examination Surveys, 1960 to 1991. JAMA. 272:205–211.[Abstract]
  2. Pi-Sunyer FX. 1993 Medical hazards of obesity. Ann Int Med. 119:655–660.[Medline]
  3. Vague J. 1947 Les obésités. Etudes Biométrique. Biol. Méd. 36:1–47.
  4. Björntorp P. 1987 The association between obesity, adipose tissue distribution, and disease. Acta Med Scand. 723[Suppl]:121–134.
  5. Krotkiewski M, Björntorp P, Sjöström L, Smith U. 1983 Impact of obesity on metabolism in men and women: importance of regional adipose tissue distribution. J Clin Invest. 72:1150–1158.[Medline]
  6. Dowling HJ, Fried SK, Pi-Sunyer FX. 1995 Insulin resistance in adipocytes of obese women: effects of body fat distribution and race. Metabolism. 44:987–995.[Medline]
  7. Albu J, Murphy L, Fraeger D, Johnson JA, Pi-Sunyer FX. 1997 Visceral fat and race-dependent health risks in obese, non-diabetic, premenopausal women. Diabetes. 46:456–462.[Abstract]
  8. Lapidus L, Bengtsson C, Larsson B, Pennert K, Rybo E, Sjöström L. 1984 Distribution of adipose tissue and risk of cardiovascular disease and death: a 12-year follow up of participants in the population study of women in Gothenburg, Sweden. Br Med J. 289:1257–1261.[Medline]
  9. Zhang Y, Proenca P, Maffei M, Barone M, Leopold L, Friedman JM. 1994 Positional cloning of the mouse obese gene and its human homologue. Nature. 372:425–432.[CrossRef][Medline]
  10. Tartaglia LA, Dembski M, Weng X et al. 1993 Identification and expression cloning of a leptin receptor, OB-R. Cell. 83:1263–1271.
  11. Bray GA, York DA. 1997 Leptin and clinical medicine: a new piece in the puzzle of obesity. J Clin Endocrinol Metab. 82:2771–1776.[Free Full Text]
  12. Hale L, Becker GW, Browsher RR, et al. 1996 Evidence of free and bound leptin in human circulation. Studies in lean and obese subjects and during short-term fasting. J Clin Invest. 98:1277–1282.[Abstract/Free Full Text]
  13. Houseknecht KL, Mantzoros CS, Kuliawat R, et al. 1996 Evidence for leptin binding to proteins in serum of rodents and humans: modulation with obesity. Diabetes. 45:1638–1643.[Abstract]
  14. Golden Pl, Maccagnan TJ, Pardridge WM. 1997 Human blood brain barrier leptin receptor. Binding and endocytosis in isolated human brain microvessels. J Clin Invest. 99:14–18.[Abstract/Free Full Text]
  15. Campfield LA, Smith FJ, Guisez Y, et al. 1995 Recombinant mouse ob protein: evidence for a peripheral signal linking adiposity and central neural networks. Science. 269:546–549.[Medline]
  16. Pelleymounter MA, Cullen MJ, Baker MB, et al. 1993 Effect of the obese gene product on body weight regulation in ob/ob mice. Science. 269:540–543.
  17. Stephens TW, Bahinski M, Bristow PK, et al. 1995 The role of neuropeptide Y in the antiobesity action of the obese gene product. Nature. 377:530–534.[CrossRef][Medline]
  18. Halaas JL, Gajiwala KS, Maffei M, et al. 1995 Weight-reducing effect of the plasma protein encoded by the obese gene. Science. 269:543–546.[Medline]
  19. Levin N, Nelson C, Gurney A, et al. 1996 Decreased food intake does not completely account for adiposity reduction after ob protein infusion. Proc Natl Acad Sci USA. 93:1726–1730.[Abstract/Free Full Text]
  20. Weigle DS, Bukowski TR, Foster DC, et al. 1995 Recombinant ob protein reduces feeding and body weight in the ob/ob mouse. J Clin Invest. 96:2065–2070.[Medline]
  21. Chua SC, Chung WK, Wu-Peng S, et al. 1996 Phenotypes of mouse diabetes and rat fatty due to mutations in the ob (leptin) receptor. Science. 271:994–996.[Abstract]
  22. Satoh N, Ogawa Y, Katsuura G, et al. 1997 Pathophysiological significance of the obese gene product, leptin, in ventromedial hypothalamus (VMH)-lesioned rats. Endocrinology. 138:947–954.[Abstract/Free Full Text]
  23. Lee GH, Proenca P, Montez JM, et al. 1996 Abnormal splicing of the leptin receptor in diabetic mice. Nature. 379:632–635.[CrossRef][Medline]
  24. Ghilardi N, Ziegler S, Wiestner A, et al. 1996 Defective STAT signaling by the leptin receptor in diabetic mice. Proc Natl Acad Sci USA. 93:6231–6235.[Abstract/Free Full Text]
  25. Chen H, Charlat O, Tartaglia LA, et al. 1996 Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell. 84:491–495.[Medline]
  26. Fei H, Okano HJ, Li C, et al. 1997 Anatomic localization of alternatively spliced leptin receptors (Ob-R) in mouse brain and other tissues. Proc Natl Acad Sci USA. 94:7001–7005.[Abstract/Free Full Text]
  27. Hoggard N, Mercer JG, Rayner DV, et al. 1997 Localization of leptin receptor mRNA splice variants in murine peripheral tissues by RT-PCR and in situ hybridization. Bioch Biophys Res Communications. 232:387–397.
  28. Mercer JG, Hoggard N, Williams L, et al. 1996 Localization of leptin receptor mRNA and the long form splice variant (Ob-Rb) in mouse hypothalamus and adjacent brain regions by in situ hybridization. FEBS letters. 387:113–116.[CrossRef][Medline]
  29. Schwartz M, Baskin DG, Bukowsli TR, et al. 1996 Specificity of leptin action on elevated blood glucose levels and hypothalamic neuropeptide Y action on elevated blood glucose levels and hypothalamic neuropeptide Y gene expression in ob/ob mice. Diabetes. 45:531–535.[Abstract]
  30. Maffei M, Halaas E, Ravussin E, et al. 1995 Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med. 1:1155–1161.[Medline]
  31. Schwartz MW, Seeley RJ, Campfield LA, Burn P, Baskin DG. 1996 Identification of targets of leptin action in rat hypothalamus. J Clin Invest. 98:1101–1106.[Abstract/Free Full Text]
  32. Pritchard TC, Plat-Salaman CR, Smith FJ, Moschera J, Campfield LA, Scott TR. 1997 The effect of long-acting modified ob protein on spontaneous feeding in the macaque. Abstract: Society for the Study of Ingestive Behavior meeting.
  33. Amgen press release. 1 Amgen Center Drive, Thousand Oaks, CA 91320. 1997.
  34. Licinio J, Mantzoros C, Negrao AB, et al. 1997 Human leptin levels are pulsatile and inversely related to pituitary-adrenal function. Nat Med. 3:575–579.[Medline]
  35. Campfield LA, Smith FJ, Burn P. 1996 The ob protein (leptin) pathway—a link between adipose tissue mass and central neural networks. Horm Metab Res. 28:619–632.[Medline]
  36. Rosenbaum M, Nicolson M, Hirsch J, Murphy E, Chu F, Leibel RL. 1997 Effects of weight change on plasma leptin concentration, and energy expenditure. J Clin Endocrinol Metab. 82:3647–3654.[Abstract/Free Full Text]
  37. Montague CT, Farooqi IS, Whitehead JP, et al. 1997 Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature. 387:292–295.[CrossRef][Medline]
  38. Clément K, Vaisse C, Lahlou N, et al. 1998 A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature. 392:398–401.[CrossRef][Medline]
  39. Maffei M, Stoffel M, Barone M, et al. 1996 Absence of mutations in the ob gene in obese/diabetic subjects. Diabetes. 45:679–682.[Abstract]
  40. Considine RV, Considine EL, Williams CJ, et al. 1996 The hypothalamic leptin receptor in humans: identification of incidental sequence polymorphisms and absence of the db/db mouse and fa/fa mutations. Diabetes. 45:992–994.[Abstract]
  41. Rohner-Jeanrenaud F, Cusin I, Sainsbury A, Zakrzewska KE, Jeanrenaud B. 1996 The loop system between neuropeptide Y and leptin in normal and obese rodents. Horm Metab Res. 28:642–648.[Medline]
  42. Fan W, Boston BA, Kesterson RA, et al. 1997 Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature. 385:165–168.[CrossRef][Medline]
  43. Lonnqvist F, Arner P, Nordfors L, Schalling M. 1995 Over expression of the obese (ob) gene in adipose tissue of human obese subjects. Nat Med. 1:950–953.[Medline]
  44. Boden G, Chen X, Mozzoli M, Ryan I. 1996 Effect of fasting on serum leptin in normal human subjects. J Clin Endocrinol Metab. 81:3419–3423.[Abstract]
  45. Ravussin E, Pratley RE, Maffei M, et al. 1997 Relatively low plasma leptin concentrations precede weight gain in Pima Indians. Nat Med. 3:238–240.[Medline]
  46. Grinspoon SK, Askari H, Landt ML, et al. 1997 Effects of fasting and glucose infusion on basal and overnight leptin concentrations in normal-weight women. Am J Clin Nutr. 66:1352–1356.[Abstract]
  47. Kolaczynski JW, Ohannesian JP, Considine RV, Marco C, Caro JF. 1996 Response of leptin to short-term and prolonged overfeeding in humans. J Clin Endocrinol Metab. 81:4162–4165.[Abstract]
  48. Laughlin GA, Yen SSC. 1997 Hypoleptinemia in women athletes: absence of a diurnal rhythm with amenorrhea. J Clin Endocrinol Metab. 82:318–321.[Abstract/Free Full Text]
  49. Schoeller DA, Cella LK, Sinha MK, Caro JF. 1997 Entrainment of the diurnal rhythm of serum leptin to meal timing. J Clin Invest. 100:1882–1887.[Abstract/Free Full Text]
  50. Considine RV, Sinha MK, Heiman ML, et al. 1996 Serum immunoreactive-leptin concentrations in normal-weight and obese humans. New Eng J Med. 334:292–295.[Abstract/Free Full Text]
  51. Takahashi M, Funahashi T, Shimomura I, Miyaoka K, Matsuzawa Y. 1996 Plasma leptin levels and body fat distribution. Horm Met Res. 28:751–752.[Medline]
  52. Hube F, Lietz U, Igel M, et al. 1996 Difference in leptin mRNA levels between omental and subcutaneous abdominal adipose tissue from obese humans. Horm Met Res. 28:690–693.[Medline]
  53. Montague CT, Prins JB, Sanders L, Digby JE, O’Rahilly S. 1997 Depot- and sex-specific differences in human leptin mRNA expression. Implication for the control of regional fat distribution. Diabetes. 46:342–347.[Abstract]
  54. Hamilton BS, Paglia D, Kwan AYM, Deitel M. 1995 Increased obese mRNA expression in omental fat cells from massively obese humans. Nature Med. 1:953–956.[Medline]
  55. Aversa A, Caprio M, Strollo F, et al. 1997 Leptin levels in humans: correlation with body fat distribution measured by dual-energy x ray absorptiometry (DEXA). The 79th Annual Meeting of The Endocrine Society Meeting. P2–534.
  56. Lonnqvist F, Wennlund A, Arner P. 1996 Relationship between circulating leptin and peripheral fat distribution in obese subjects. Int J Ob. 21:255–260.
  57. Cusin I, Sainsbury, Doyle P, Rohner-Jeanrenaud F, Jeanrenaud B. 1995 The ob gene and insulin: a relationship leading to clues to the understanding of obesity. Diabetes. 44:1467–1470.[Abstract]
  58. Dagogo-Jack S, Fanelli C, Paramore D, Brothers J, Landt M. 1996 Plasma leptin and insulin relationships in obese and non obese humans. Diabetes. 45:695–698.[Abstract]
  59. Ryan AS, Elahi D. 1996 The effect of acute hyperglycemia and hyperinsulinemia on plasma leptin levels: its relationship with body fat, visceral adiposity, and age in women. J Clin Endocrinol Metab. 81:4433–4438.[Abstract]
  60. Kennedy A, Gettys TW, Watson P, et al. 1997 The metabolic significance of leptin in humans: gender-based differences in relationship to adiposity, insulin sensitivity, and energy expenditure. J Clin Endocrinol Metab. 82(4):1293–1300.
  61. Segal KR, Landt M, Klein S. 1996 Relationship between insulin sensitivity and plasma leptin concentration in lean and obese men. Diabetes. 45:988–991.[Abstract]
  62. Malmstrom R, Taskinen MR, Karonen SL, Yki-Jarvinen H. 1996 Insulin increases plasma leptin concentrations in normal subjects and patients with NIDDM. Diabetologia. 39(8):993–996.
  63. Utriainen T, Malmstrom R, Makimattila S, Yki-Jarvinen H. 1996 Supraphysiological hyperinsulinemia increases plasma leptin concentrations after 4 h in normal subjects. Diabetes. 45:1364–1366.[Abstract]
  64. Boden G, Chen X, Kolanczynski J, Polansky M. 1997 Effects of prolonged hyperinsulinemia on serum leptin in normal human subjects. J Clin Invest. 100:1107–1113.[Abstract/Free Full Text]
  65. Saad MF, Khan A, Sharma A, et al. 1998 Physiological insulinemia acutely modulates plasma leptin. Diabetes. 47:544–549.[Abstract]
  66. Clapham JC, Smith SA, Moore GBT, Hughes MG, Azam H, Scott A, Jung RT. 1997 Plasma leptin concentrations and ob gene expression in subcutaneous adipose tissue are not regulated acutely by physiological hyperinsulinemia in lean and obese humans. Int J Obes. 21:179–183.[CrossRef]
  67. Kolaczynski JW, Nyce MR, Considine RV, et al. 1996 Acute and chronic effect of insulin on leptin production in humans: Studies in vivo and in vitro. Diabetes. 45:699–701.[Abstract]
  68. Pratley RE, Nicolson M, Bogardus C, Ravussin E. 1996 Effects of acute hyperinsulinemia on plasma leptin concentrations in insulin-sensitive and insulin-resistant Pima Indians. J Clin Endocrinol Metab. 81:4418–4421.[Abstract]
  69. Haffner SM, Stern MP, Miettinen H, Wei M, Gingerich RL. 1996 Leptin concentrations in diabetic and non-diabetic Mexican-Americans. Diabetes. 45:822–824.[Abstract]
  70. Cohen B, Novick D, Rubinstein M. 1996 Modulation of insulin activities by leptin. Science. 274:1185–1188.[Abstract/Free Full Text]
  71. Taylor SI, Barr V, Reitman M. 1996 Does leptin contribute to diabetes caused by obesity? Science. 274:1151–1152.[Free Full Text]
  72. Zierath JR, Frevert EU, Ryder JW, Berggren P-O, Kahn BB. 1998 Evidence against a direct effect of leptin on glucose transport in skeletal muscle and adipocytes. Diabetes. 47:1–4.[Abstract]
  73. Castonguay TW, Dallman M, Stern JS. 1984 Corticosterone prevents body weight loss and diminished fat appetite following adrenalectomy. Nutrition & Behavior. 2:115–125.
  74. Freedman MR, Horwitz BA, Stern JS. 1986 Effect of adrenalectomy and glucocorticoid replacement on development of obesity. Am J Physiol. 250:R595–R607.
  75. Vague J, Meignen JM, Negrin JF, Thomas M, Tramoni M, Jubelin J. 1985 Le diabète de la femme androide. Trente-cinq ans après. Sem Hop Paris. 61:1015–1025.
  76. Marin P, Darin N, Amemiya T, Andersson B, Jern S, Björntorp P. 1992 Cortisol regulation in relation to body fat distribution in obese premenopausal women. Metabolism. 8:882–886.
  77. Pasquali R, Cantobelli S, Casimirri F, et al. 1993 The hypothalamic-pituitary adrenal axis in obese women with different patterns of body fat distribution. J Clin Endocrinol Metab. 77:341–346.[Abstract]
  78. Laferrère B, Lahlou N, Saltiel H, Roger M, Basdevant A, Guy-Grand B. 1994 Hypersensitivity of the corticotropic axis to the serotoninergic agent clomipramine in obese women. Obes Res. 2:328–336.
  79. Kopelman PG. 1988 Neuroendocrine functions in obesity. Clin Endocrinol. 28:675–679.[Medline]
  80. Krotkiewski M, Butruck E, Zemrzuska Z. 1966 Les fonctions cortico-surrénales dans les divers types morphologiques d’obésité, Le Diabète. 19:229–233.
  81. Leal-Cerro A, Considine RV, Peino R, et al. 1996 Serum immunoreactive-leptin levels are increased in patients with Cushing’s syndrome. Horm Metab Res. 28:711–713.[Medline]
  82. Miell JP, Englaro P, Blum WF. 1996 Dexamethasone induces an acute and sustained rise in circulating leptin levels in normal human subjects. Horm Met Res. 28:704–707.[Medline]
  83. Kiess W, Englaro P, Hanistsch S, Rascher W, Attanasio A, Blum WF. 1996 High leptin concentrations in serum of very obese children are further stimulated by dexamethasone. Horm Metab Res. 28:708–710.[Medline]
  84. Larsson H, Ahrén B. 1996 Short-term dexamethasone treatment increases plasma leptin independently of changes in insulin sensitivity in healthy women. J Clin Endocrinol Metab. 81:4428–4431.[Abstract]
  85. Papaspyrou-Rao S, Schneider SH, Petersen RN, Fried SK. 1997 Dexamethasone increases leptin expression in humans in vivo. J Clin Endocrinol Metab. 82:1635–1637.[Abstract/Free Full Text]
  86. Dagogo-Jack S, Selke G, Melson A, Newcomer JW. 1997 Robust leptin secretory responses to dexamethasone in obese subjects. J Clin Endocrinol Metab. 82:3230–3233.[Abstract/Free Full Text]
  87. Zakzrewska KE, Cusin I, Sainsbury A, Rohner-Jeanrenaud F, Jeanrenaud B. 1997 Glucocorticoids as counter regulatory hormones of leptin: towards an understanding of leptin resistance. Diabetes. 46:717–719.[Abstract]
  88. Haynes WG, Morgan DA, Walsh SA, Sivitz WI, Mark AL. 1998 Cardiovascular consequences of obesity: role of leptin. Clin Exp Pharmacol Physiol. 25:65–69.[Medline]
  89. de Courten M, Zimmet P, Hodge A, et al. 1997 Hyperleptinemia: missing link in the metabolic syndrome? Diabetes Med. 14:200–208.[CrossRef][Medline]
  90. Ostlund RE, Yang JW, Klein S, Gingerich R. 1996 Relation between plasma leptin concentration and body fat, gender, diet, age, and metabolic covariates. J Clin Endocrinol Metab. 81:3909–3913.[Abstract]
  91. Couillard C, Maurieges P, Prud’homme D, et al. 1997 Plasma leptin concentrations: gender differences and associations with metabolic risk factors for cardiovascular disease. Diabetologia. 40:1178–1184.[CrossRef][Medline]
  92. Rainwater DL, Commuzzie AG, VandeBerg JL, Mahaney MC, Blangero J. 1997 Serum leptin levels are independently correlated with two measures of HDL. Atherosclerosis. 32:237–243.
  93. Gong DW, He Y, Karas M, Reitman M. 1997 Uncoupling protein-3 is a mediator of thermogenesis regulated by thyroid hormone, ß3-adrenergic agonists, and leptin. J Biol Chem. 272:24129–24132.[Abstract/Free Full Text]