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Editorial

See corresponding article on page 794.

Do circulating leptin concentrations reflect body adiposity or


energy flux?1,2
Allen S Levine and Charles J Billington

Leptin was first identified as the protein missing in the obese These measures also did not seem to be correlated with the
mouse (ob/ob), with resulting hyperphagia, diminished energy length of the diet restriction. Thus, Keim et al found a significant
expenditure, and increased adiposity (1). Leptin administration to negative correlation between leptin and measures of hunger-
ob/ob mice appeared to correct most abnormalities and lower body related variables.
weight. These observations initially raised hopes that some human How then can one interpret the role that leptin plays in regu-
obesity occurred for similar reasons and could be treated in the lating energy metabolism? It is a regulator that is missing from
same way. However, nearly all studies of obese humans show a obese mice, whereas concentrations are elevated in most obese
strong and consistent positive relation between plasma leptin con- humans, and it reflects adiposity during a weight-stable period,
centrations and adipose mass (2, 3). One potential reason for lep- but does not reflect adiposity during a period of food restriction.
tin overproduction is a defect in the leptin receptor, such as in dia- It appears likely that the changed state of energy balance is a key
betic mice (db/db) (4), but leptin receptor defects are unlikely to variable. When energy balance is in steady state, leptin concen-
account for more than a small number of human cases of obesity. trations correlate well with the amount of adipose tissue. Signi-
Therefore, current research aims to understand the role of leptin in ficant changes in energy balance with nonsteady state condi-
mechanisms regulating appetite and body weight. tions, particularly total-body energy loss, appear to decrease
The leptin receptor is notably expressed in hypothalamic serum leptin out of proportion to changes in fat mass.
regions known to be involved in feeding behavior (5). Intracere- A variety of hormones, regulators, and metabolites change
broventricular leptin injection decreases food intake in nonobese quickly during periods of either acute food deprivation or chron-
rats and affects body weight for as long as 6 d (6). Leptin recep- ic food restriction. For example, serum cholesterol concentra-
tors and neuropeptide Y cell bodies are both found in the arcuate tions drop with food restriction, before major decreases in body
nucleus of the hypothalamus (5, 7). Because leptin decreases weight occur. Similar changes occur in insulin, thyroid hormone,
feeding and increases energy expenditure whereas neuropeptide blood pressure, and a variety of constitutive proteins with short
Y does the opposite, several investigators have suggested that half-lives. Sympathetic nervous system activity is also dimin-
leptin may affect energy balance by altering neuropeptide Y sig- ished during energy deprivation. Thus, leptin may be responding
naling pathways. Recent data confirm that one important way as other proteins do to the energy status of the individual, which
leptin affects energy homeostasis is by decreasing neuropeptide eventually is reflected in body weight. It is also possible that lep-
Y biosynthesis in the arcuate nucleus (8). tin secretion from adipose cells is in part regulated by other fac-
One hypothesis about leptin function is that leptin provides tors such as the sympathetic nervous system, insulin, or gluco-
information about the size of body fat stores to regulatory mech- corticoids (10). A recent report by Wang et al (11) suggests that
anisms in the brain. That hypothesis has to be tempered by many the hexosamine biosynthetic pathway may serve as a nutrient
reports showing that serum leptin concentrations are reduced by sensor that regulates leptin gene expression in muscle and fat.
food deprivation. Leptin concentrations decrease after a 23 d The end product of this pathway, UDP-N-acetylglucosamine,
fast or very low energy intakes from 7 d to as long as 3 mo (for results in rapid and marked increases in leptin messenger RNA
review, see reference 9). In these situations, leptin concentrations and protein. Also, leptin synthesis is stimulated with hypergly-
are disproportionate to changes in adiposity. cemia or hyperlipidemia, which also increases concentrations of
In this issue of the Journal, Keim et al (9) report that circulat- UDP-N-acetylglucosamine in rodents. Thus, leptin concentra-
ing leptin concentrations decreased during a prolonged, moder- tions may be influenced by a nutrient sensing mechanism, rather
ate energy deficit in 12 healthy, overweight women. After 1 wk than being a simple reflection of total body adiposity.
of the restricted diet, body weight and fat mass had not changed
significantly, yet leptin and insulin concentrations had decreased 1
From the Minnesota Obesity Center, VA Medical Center, Minneapolis,
by 57% and 49%, respectively. After 12 wk of diet restriction, and the Departments of Psychiatry and Medicine, University Of Minnesota,
leptin and insulin concentrations were not significantly below Minneapolis.
concentrations noted after 1 wk. As one would expect, self- 2
Address reprint request to AS Levine, Minnesota Obesity Center, VA
reports of hunger, desire to eat, and a measure of how much one Medical Center (151), 1 Veterans Drive, Minneapolis, MN 55417. E-mail:
would like to eat increased during the chronic restriction state. allenl@tc.umn.edu.

Am J Clin Nutr 1998;68:7612. Printed in USA. 1998 American Society for Clinical Nutrition 761
762 EDITORIAL

The study by Keim et al (9) does support the notion that lep- rodent: measurement of plasma leptin and ob RNA in obese and
tin acts as a regulator of food intake in humans because there was weight-reduced subjects. Nat Med 1995;1:115561.
an indirect correlation between self-reported hunger status and 3. Havel PJ, Kasim-Karakas S, Mueller W, Johnson PR, Gingerich RL,
Stern JS. Relationship of plasma leptin to plasma insulin and adipos-
leptin concentrations. Of course, such a correlation does not
ity in normal weight and overweight women: effects of dietary fat con-
establish a cause-effect relation. Because insulin also decreased tent and sustained weight loss. J Clin Endocrinol Metab 1996;
within 1 wk of food restriction, and a satiating effect of insulin 81:440613.
has been reported (12), it is possible that insulin and perhaps 4. Lee GH, Proenca R, Montez JM, et al. Abnormal splicing of the leptin
other peripheral signals also participated in the observed effects. receptor in diabetic mice. Nature 1996;379:6325.
However, Keim et al did not find that plasma leptin correlated 5. Schwartz MW, Seeley RJ, Campfield LA, Burn P, Baskin DG. Identi-
with changes in plasma insulin. fication of targets of leptin action in rat hypothalamus. J Clin Invest
1996;98:11016.
In a phase I clinical trial reported at the 58th Annual Scientif-
6. Seeley RJ, van Dijk G, Campfield LA, et al. Intraventricular leptin
ic Sessions of the American Diabetes Association in Chicago reduces food intake and body weight of lean rats but not obese Zucker
(June 1998), daily leptin injection in obese humans who were rats. Horm Metab Res 1996;28:6648.
dieting resulted in an average weight loss of 15.6 lb (<7.1 kg) 7. Allen JM, Koenig JI. Central and peripheral significance of neuropep-
after 6 mo compared with a weight loss of 3.7 lb (<1.7 kg) in the tide Y and its related peptides. New York: New York Academy of Sci-
placebo group. Leptin did not result in weight loss in all obese ences, 1990.
subjects, which is not surprising because the etiology of obesity 8. Kotz CM, Briggs JE, Pomonis JD, Grace MK, Levine AS, Billington
CJ. Neural site of leptin influence on neuropeptide Y signaling path-
is multifactorial. The work of Keim et al indicates that circulat- ways altering feeding and uncoupling protein. Am J Physiol
ing concentrations of leptin may decrease relatively quickly in 1998;275:R47884.
response to energy restriction, and could contribute to a feeling 9. Keim NL, Stern JS, Havel PJ. Relation between circulating leptin con-
of hunger. Unfortunately, not all obese persons overeat because centrations and appetite during a prolonged, moderate energy deficit in
of hunger, which might explain why neither leptin nor any one women. Am J Clin Nutr 1998;68:794801.
substance can be used as a cure for obesity. 10. Slieker LJ, Sloop KW, Surface PL, et al. Regulation of expression of
ob mRNA and protein by glucocorticoids and cAMP. J Biol Chem
1996;271:53014.
REFERENCES 11. Wang J, Liu R, Hawkins M, Barzilai N, Rossetti L. A nutrient-sensing
pathway regulates leptin gene expression in muscle and fat. Nature
1. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman 1998;393:6848.
JM. Positional cloning of the mouse obese gene and its human 12. Schwartz MW, Figlewicz DP, Baskin DG, Woods SC, Porte DJ.
homologue. Nature 1994;372:42532. Insulin in the brain: a hormonal regulator of energy balance. Endocr
2. Maffei M, Halaas J, Ravussin E, et al. Leptin levels in human and Rev 1992;13:387414.

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