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Endocrinology Vol. 138, No. 3 1190-1193
Copyright © 1997 by The Endocrine Society

Articles

Leptin Treatment Rescues the Sterility of Genetically Obese ob/ob Males1

Khalid Mounzih, Ronghua Lu and Farid F. Chehab1

University of California, San Francisco, Department of Laboratory Medicine, San Francisco, California 94143-0134

Address all correspondence and requests for reprints to: Dr. Farid F. Chehab, 505 Parnassus Avenue, University of California, San Francisco, Department of Laboratory Medicine, San Francisco, California 94143-0134. E-mail: chehab{at}pangloss.ucsf.edu


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Discussion
 References
 
Leptin, a hormone secreted from white adipose tissue, has been shown to normalize the body weight of ob/ob but not db/db mice as postulated by Coleman in his classical parabiosis experiments. The major effect of leptin is therefore to decrease food intake, thus resulting in a breakdown of fat stores. Recently, we have suggested that leptin plays a role in reproductive physiology based on the observation that leptin treatment but not food restriction rescues the sterility of ob/ob females. In the present communication, we treated sterile ob/ob males with leptin and asked whether fertility could be induced, thus selecting their reproductive ability as the endpoint of the experiment. Our results show that all food-restricted ob/ob males are unable to impregnate normal C57BL/6J females. However, all leptin-treated ob/ob males fertilized normal females mice that carried out normal pregnancies and deliveries, demonstrating that the reproductive capacity of ob/ob males was corrected only with leptin treatment. Furthermore, reproductive indices such as testicular weight and histology are normalized in leptin-treated animals. Therefore, as in ob/ob females, leptin plays a significant role in the male mouse reproductive pathways.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Discussion
 References
 
MALE AND FEMALE ob/ob and db/db mouse models that display morbid obesity and diabetes are sterile (1, 2, 3). These mice share many pathological features with human obesity, which is often marked by disturbances of reproductive function. Since the cloning of the ob and db genes (4, 5), little attention has been given to the sterility component of this syndrome. Previous studies have suggested that the underlying nature of the sterility defect in ob/ob mice was central rather than peripheral as evidenced by the low levels of FSH, LH, and circulating steroids (6). Because low levels of gonadal steroids should stimulate gonadotropin secretion in the presence of functioning feedback mechanisms at the hypothalamic-pituitary gonadal axis, the ob/ob mouse is deficient in this respect. Physiologically, the defect was attributed to a hypothalamic deficiency of GnRH secretion as shown by the ability of ob/ob males to release LH from the pituitary when stimulated with exogenous GnRH, although a defective pituitary site was not completely ruled out (7). Whereas ob/ob females are invariably sterile, a few ob/ob males were reported to occasionally reproduce (8). Introduction of leptin, the product of the ob gene, to leptin deficient ob/ob mice not only restores normal body weight (9, 10) but also corrects the sterility of adult female ob/ob mice (11), suggesting that leptin is involved in reproductive physiology. We report here that leptin treatment of adult ob/ob males corrects their sterility, an effect that is mediated at least partly by a normalization in testicular weight, spermatogenesis and Leydig cells morphology.\.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Discussion
 References
 
Leptin treatment and food restriction of ob/ob males
Experiments were approved by the UCSF Committee on Animal Research. The animals were purchased from the Jackson Laboratories (Bar Harbor, ME) and maintained each in individual cages at the UCSF Animal Care Facility under a 12-h dark light regimen (lights on at 0600 h, off at 1800 h). Human recombinant leptin was prepared exactly as previously described (11) from extracts of recombinant E. coli carrying a bacterial expression vector encoding the cDNA sequences of the mature form of human leptin. Ten morbidly obese adult homozygous ob/ob males housed in individual cages were equally divided into food-restricted (ob/ob 1–5) and a leptin-treated (ob/ob 6–10) groups. To accelerate weight loss, the recombinant protein was injected daily ip at a single dose of 20 µg/g initial body weight, which represents twice the dose administered previously to ob/ob females (11). The treatment was for 60 days to allow enough time for the food restricted ob/ob males to stabilize their body weight loss. Leptin-treated ob/ob males had continuous access to food, whereas food-restricted ob/ob males were pair-fed to the leptin-treated group and allowed to consume daily 1 g of food (Purina-Mills, FormuLab Diet 5008) for 46 days and 3 g for the remaining 14 days. Water was provided without any restriction to both groups. In addition, 5 ob/ob males were treated for 12 days with an equal volume (0.2–0.5 ml) of PBS vehicle solution.

Matings of ob/ob mice
After 12 days of leptin treatment, two adult C57 BL/6J females (6–8 months old, regularly cycling) were placed with each ob/ob male from both groups. Each of the breeder females had 1–2 successful pregnancies before mating with the ob/ob males. Females with food-restricted ob/ob males were placed in the cage between 1700 h and 0600 h for mating after each ob/ob male had consumed the gram of food. All females were removed the next morning and placed in cages where they had access to food which females with the food-restricted males lacked during the dark period. This cycle was repeated throughout the treatment. Females were earmarked and always paired with the same ob/ob male. Presence of copulatory plugs were checked daily between 0800 h and 1000 h. Potential pregnancies were monitored up to 20 days after detection of the plug for an increase in body weight and delivery of pups.

Organ weights and histology
To determine some of the parameters that contributed to their fertility, control, and leptin-treated ob/ob mice were killed by an overdose of 2.5% Avertin at day 61 along with five lean male C57/BL mice and three untreated ob/ob males that were fed ad libitum. To gain further insights into the effects of leptin treatment on the anatomy of the testis, histological examination of testicular sections from lean, untreated ob/ob, food restricted ob/ob and leptin treated ob/ob mice were carried out. The seminal vesicles and testis of all animals were weighed and histology of the testis examined. The seminal vesicles and testis were dissected and weighed immediately. The testis were then fixed in fresh 4% paraformaldehyde in PBS for 48 h and processed for paraffin embedding, sectioning, and hematoxylin/eosin staining. Statistics were determined by two-sample unpaired Student’s t test.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Discussion
 References
 
Food consumption and body weight of ob/ob males
The food-restricted and leptin-treated mice entered the treatment with body weights of 68.7 ± 1.2 g and 65.6 ± 2.2 g, respectively (means ± SEM). Mean daily food intake of leptin-treated ob/ob males during the first 12 days of treatment consisted of 0.8 ± 0.1 g (Table 1Go). Thus, food-restricted ob/ob males consuming the daily allotted gram of food pellet represent pair-fed controls, considering that a small amount of food is lost during its consumption. After 12 days of treatment, animals in the food-restricted and leptin groups had lost, respectively, 24.2 ± 0.5% and 32.1 ± 1.2% of their initial body weight (Fig. 1Go). Long term leptin treatment resulted in an increase of food consumption to approximately 2.9 ± 0.3 g at day 45 (Table 1Go), which was used as a reference to increase the allotment of food to the food-restricted males for the last 2 weeks of treatment. Both leptin and food restriction treatments resulted in different stabilization of body weights after respective reductions of 56.4 ± 1.0% and 49.6 ± 1.2% (P = 0.002) showing that leptin treatment was more effective than food restriction. On the other hand, the body weights of the PBS-treated ob/ob mice did not significantly change over the first 12 days of treatment (data not shown). Because no weight loss was observed in these mice, they were excluded from subsequent matings.


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  		Table 1. Daily food consumption (in grams) of the 5 leptin-treated ob/ob males during the first 12 days and at day 45 of the treatment.

 


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  		Figure 1. Effect of leptin treatment or food restriction on the body weights of ob/ob males. Body weights are expressed as means and SEM of five animals per group. Standard errors for most points were too small to be shown on the plotted scale.

 
Fertility of ob/ob males
Food restriction of ob/ob males resulted in a significant weight loss of 40.6 ± 0.5% at 30 days and 48.1 ± 1.8% at 60 days. Monitoring of body weight and food intake of the lean females revealed that they maintained a constant weight and consumed their food during the day because food was not available in the dark period when they were placed with the food-restricted ob/ob males (data not shown). Mating of the five leptin-treated ob/ob males with the 10 lean females resulted in copulatory plugs, pregnancies, and deliveries in all the breeder females. However, none of the lean females that were mated with the food-restricted males had a copulatory plug nor became pregnant (Table 2Go).


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  		Table 2. Litter sizes from lean females mated to ob/ob males in both groups

 
Organ weights and testicular histology
Differences in seminal vesicles weights among the four groups were not statistically significant. However, testis weight, which is mostly indicative of overall spermatogenic activity and testosterone content, was significantly different between lean and untreated ob/ob mice (P < 0.001) and food-restricted vs. leptin-treated ob/ob mice (P < 0.001) as shown in Table 3Go. Interestingly, comparison of the untreated ob/ob and food restricted ob/ob mice resulted in a 60% increase in testicular weight of the latter group (P < 0.009) without, however, correction of their sterility. Furthermore, two prominent histological features shown in Fig. 2Go are noticeable. First, the lumen of the seminiferous tubules in the untreated and food restricted ob/ob males appear hollow and contain strikingly less sperm than the lean male mouse. Second, the interstitial Leydig cells of the obese mice are atrophied due visibly to a shrinkage in their cytoplasm (Fig. 2Go). In contrast, the seminiferous tubules of the leptin-treated ob/ob males become abundant with mature sperms and the Leydig cells regain their usual morphology and clustering characteristic.


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  		Table 3. Body, seminal vesicles, and testis weights (means ± SEM) of lean C57/BL and ob/ob males either untreated, food-restricted, or leptin-treated at the end of the treatment (day 61). Weights of the seminal vesicles and testis are expressed in mg per g body weight.

 


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  		Figure 2. Hematoxylin and eosin stained sections of testis from lean, untreated ob/ob, food restricted ob/ob, and leptin-treated ob/ob mice. A, Overall appearance of seminiferous tubules. The tubules are hollow and contain little sperm in the untreated and food-restricted ob/ob males. Lean and leptin-treated ob/ob males show normal tubules with abundant sperm. Magnification, 100x. B, Seminiferous tubules and Leydig cells. This view shows the sperm deficient lumen of the seminiferous tubules and shrunk interstitial Leydig cells in untreated and food-restricted ob/ob males. Leptin-treated ob/ob males regain a testicular histology comparable with the lean wild-type male. Magnification, 400x. C, Magnification showing interstitial Leydig cells. The untreated and food-restricted ob/ob males show cytoplasm shrinkage of the Leydig cells, whereas the leptin-treated ob/ob males have normal Leydig cells identical to lean males. Magnification, 1000x.

 

   Discussion
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Discussion
References
 
The present study shows that leptin treatment rescues the sterility of ob/ob males similarly to its effects on ob/ob females (11), thus extending the role of leptin in male reproduction. One effect of the leptin-induced fertility treatment of ob/ob males is a normalization of testicular weight and function by allowing regeneration of Leydig cells. Previous studies have shown that the overall structure of the ob/ob testis is abnormal and characterized most aberrantly by multinucleated spermatids, few spermatozoa, and a small amount of interstitial Leydig tissue (3) reduced by more than 50% (12). Furthermore, weight loss in ob/ob males due to food restriction did not ameliorate their abnormal histology (12, 13) nor infertility. Thus, despite their weight loss, food-restricted adult ob/ob males failed to fertilize normal females. We cannot rule out the possibility that the stress induced by food restriction on the ob/ob males or the food consumption during the day period of the breeder females could have contributed to this effect. It is also possible that the increase in pair feeding after day 45, possibly due to leptin resistance, may have resulted in stabilization of body weight above that of leptin-treated mice. Unlike previous studies that showed that two ob/ob males need to be food restricted from 6 weeks of age and maintained at a weight of 26–30 g to achieve fertility (8), our studies show that leptin-mediated correction of the sterility of ob/ob mice occurred despite an initial morbidly obese state, thus demonstrating that the block imposed on the reproductive system is not permanent and can be removed with leptin treatment. The effects of a 2-week leptin treatment was recently shown to result in a rise of FSH and LH levels in ob/ob males and ob/ob females, respectively (14), complementing our previous and present findings about the rescuing effects of leptin on the sterility of ob/ob mice. However, the mechanisms by which leptin mediates these effects remain to be determined although the primary candidate site of action is the hypothalamic-pituitary axis (7, 15), which has long been postulated to be defective in the ob/ob mouse. A peripheral defect of leptin and its receptor(s) in the ovary is excluded since the ovaries of ob/ob (16) and db/db females are functional when transplanted into normal females.

Our findings involving leptin in reproduction are reminiscent of examples linking obesity with reproductive disturbances in males and females (17, 18). On the other hand, leanness or too little fat in women, was shown to be associated with menstrual abnormalities (19, 20), decreased hypothalamic GnRH secretion in male marathon runners (21), and low serum testosterone in male wrestlers (22). These and previous observations (23) linking very low adiposity with impaired reproductive function in women have led to the critical fat hypothesis that relates an ideal percentage of body fat to menarche. Because leptin levels reflect adipose mass (24, 25), extreme losses in body fat might depress leptin levels below a threshold under which reproduction or menstruation would be interrupted. Weight gain and increases of leptin levels would presumably restore menstruation. Although the ob/ob mouse is morbidly obese, the absence of leptin from its circulation could constantly be interpreted by central neural networks as an absence of energy stores perceived as recently proposed in a starvation status (26), thus resulting in a constant prepubertal state and an ensuing shutdown of reproduction. Therefore, the main action of leptin on nutrition could be via the reproductive system, more specifically through the hypothalamic-pituitary gonadal axis that modulates secretion of gonadal steroids thereby signaling to neural networks about the capacity of energy reserves needed to trigger reproduction.


   Acknowledgments
 
We thank Dr. Richard Weiner for suggestions and comments.


   Footnotes
 
1 This work was supported partly from NIH Grant HLS-53762. Back

Received September 20, 1996.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Discussion
 References
 

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G. F. Turi, Z. Liposits, S. M. Moenter, C. Fekete, and E. Hrabovszky
Origin of Neuropeptide Y-Containing Afferents to Gonadotropin-Releasing Hormone Neurons in Male Mice
Endocrinology, November 1, 2003; 144(11): 4967 - 4974.
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M. E. Wilson, J. Fisher, K. Chikazawa, R. Yoda, A. Legendre, D. Mook, and K. G. Gould
Leptin Administration Increases Nocturnal Concentrations of Luteinizing Hormone and Growth Hormone in Juvenile Female Rhesus Monkeys
J. Clin. Endocrinol. Metab., October 1, 2003; 88(10): 4874 - 4883.
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D. R. Garris and B. L. Garris
Diabetes (db/db) Mutation-Induced Ovarian Involution: Progressive Hypercytolipidemia
Experimental Biology and Medicine, October 1, 2003; 228(9): 1040 - 1050.
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S. S. Block, J. M. Smith, R. A. Ehrhardt, M. C. Diaz, R. P. Rhoads, M. E. Van Amburgh, and Y. R. Boisclair
Nutritional and Developmental Regulation of Plasma Leptin in Dairy Cattle
J Dairy Sci, October 1, 2003; 86(10): 3206 - 3214.
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J. Zhao, T. H. Kunz, N. Tumba, L. Clamon Schulz, C. Li, M. Reeves, and E. P. Widmaier
Comparative analysis of expression and secretion of placental leptin in mammals
Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2003; 285(2): R438 - R446.
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D. R. Mann, A. O. K. Johnson, T. Gimpel, and V. D. Castracane
Changes in Circulating Leptin, Leptin Receptor, and Gonadal Hormones from Infancy until Advanced Age in Humans
J. Clin. Endocrinol. Metab., July 1, 2003; 88(7): 3339 - 3345.
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G. K. Bhat, M. L. Hamm, J. U. Igietseme, and D. R. Mann
Does Leptin Mediate the Effect of Photoperiod on Immune Function in Mice?
Biol Reprod, July 1, 2003; 69(1): 30 - 36.
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K. Kawamura, N. Sato, J. Fukuda, H. Kodama, J. Kumagai, H. Tanikawa, A. Nakamura, and T. Tanaka
Leptin Promotes the Development of Mouse Preimplantation Embryos in Vitro
Endocrinology, May 1, 2002; 143(5): 1922 - 1931.
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 Genes Dev.Home page
A. Sainsbury, C. Schwarzer, M. Couzens, A. Jenkins, S. R. Oakes, C. J. Ormandy, and H. Herzog
Y4 receptor knockout rescues fertility in ob/ob mice
Genes & Dev., May 1, 2002; 16(9): 1077 - 1088.
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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.
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 EndocrinologyHome page
J. Qiu, S. Ogus, K. Mounzih, A. Ewart-Toland, and F. F. Chehab
Leptin-Deficient Mice Backcrossed to the BALB/cJ Genetic Background Have Reduced Adiposity, Enhanced Fertility, Normal Body Temperature, and Severe Diabetes
Endocrinology, August 1, 2001; 142(8): 3421 - 3425.
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M. Wabitsch, A. Ballauff, R. Holl, W. F. Blum, E. Heinze, H. Remschmidt, and J. Hebebrand
Serum Leptin, Gonadotropin, and Testosterone Concentrations in Male Patients with Anorexia Nervosa during Weight Gain
J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 2982 - 2988.
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M. Woller, S. Tessmer, D. Neff, A. A. Nguema, B. V. Roo, and D. Waechter-Brulla
Leptin Stimulates Gonadotropin Releasing Hormone Release From Cultured Intact Hemihypothalami and Enzymatically Dispersed Neurons
Experimental Biology and Medicine, June 1, 2001; 226(6): 591 - 596.
[Abstract] [Full Text] [PDF]

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R. R. González, P. Caballero-Campo, M. Jasper, A. Mercader, L. Devoto, A. Pellicer, and C. Simon
Leptin and Leptin Receptor Are Expressed in the Human Endometrium and Endometrial Leptin Secretion Is Regulated by the Human Blastocyst
J. Clin. Endocrinol. Metab., December 1, 2000; 85(12): 4883 - 4888.
[Abstract] [Full Text]

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 EndocrinologyHome page
P. D. Raposinho, E. Castillo, V. D'alleves, P. Broqua, F. P. Pralong, and M. L. Aubert
Chronic Blockade of the Melanocortin 4 Receptor Subtype Leads to Obesity Independently of Neuropeptide Y Action, with No Adverse Effects on the Gonadotropic and Somatotropic Axes
Endocrinology, December 1, 2000; 141(12): 4419 - 4427.
[Abstract] [Full Text] [PDF]

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S. Nagatani, Y. Zeng, D. H. Keisler, D. L. Foster, and C. A. Jaffe
Leptin Regulates Pulsatile Luteinizing Hormone and Growth Hormone Secretion in the Sheep
Endocrinology, November 1, 2000; 141(11): 3965 - 3975.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
Z. Atcha, F. R. A. Cagampang, J. A. Stirland, I. D. Morris, A. N. Brooks, F. J. P. Ebling, M. Klingenspor, and A. S. I. Loudon
Leptin Acts on Metabolism in a Photoperiod-Dependent Manner, But Has No Effect on Reproductive Function in the Seasonally Breeding Siberian Hamster (Phodopus sungorus)
Endocrinology, November 1, 2000; 141(11): 4128 - 4135.
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 Mol Hum ReprodHome page
J. Alfer, F. Muller-Schottle, I. Classen-Linke, U. von Rango, L. Happel, K. Beier-Hellwig, W. Rath, and H. M. Beier
The endometrium as a novel target for leptin: differences in fertility and subfertility
Mol. Hum. Reprod., July 1, 2000; 6(7): 595 - 601.
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 EndocrinologyHome page
T. El-Hefnawy, S. Ioffe, and M. Dym
Expression of the Leptin Receptor during Germ Cell Development in the Mouse Testis
Endocrinology, July 1, 2000; 141(7): 2624 - 2630.
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P E CLAYTON and J A TRUEMAN
Leptin and puberty
Arch. Dis. Child., July 1, 2000; 83(1): 1 - 4.
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M. C. Lebrethon, E. Vandersmissen, A. Gerard, A. S. Parent, J. L. Junien, and J. P. Bourguignon
In Vitro Stimulation of the Prepubertal Rat Gonadotropin-Releasing Hormone Pulse Generator by Leptin and Neuropeptide Y through Distinct Mechanisms
Endocrinology, April 1, 2000; 141(4): 1464 - 1469.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
M. Caprio, A. M. Isidori, A. R. Carta, C. Moretti, M. L. Dufau, and A. Fabbri
Expression of Functional Leptin Receptors in Rodent Leydig Cells
Endocrinology, November 1, 1999; 140(11): 4939 - 4947.
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M. Rosenbaum and R. L. Leibel
Role of Gonadal Steroids in the Sexual Dimorphisms in Body Composition and Circulating Concentrations of Leptin
J. Clin. Endocrinol. Metab., June 1, 1999; 84(6): 1784 - 1789.
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 Am. J. Physiol. Endocrinol. Metab.Home page
W. A. Banks, R. N. McLay, A. J. Kastin, U. Sarmiento, and S. Scully
Passage of leptin across the blood-testis barrier
Am J Physiol Endocrinol Metab, June 1, 1999; 276(6): E1099 - E1104.
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P. Magni, R. Vettor, C. Pagano, A. Calcagno, E. Beretta, E. Messi, M. Zanisi, L. Martini, and M. Motta
Expression of a Leptin Receptor in Immortalized Gonadotropin-Releasing Hormone-Secreting Neurons
Endocrinology, April 1, 1999; 140(4): 1581 - 1585.
[Abstract] [Full Text]

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 EndocrinologyHome page
D. Barkan, H. Jia, A. Dantes, L. Vardimon, A. Amsterdam, and M. Rubinstein
Leptin Modulates the Glucocorticoid-Induced Ovarian Steroidogenesis
Endocrinology, April 1, 1999; 140(4): 1731 - 1738.
[Abstract] [Full Text]

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 EndocrinologyHome page
A. Ewart-Toland, K. Mounzih, J. Qiu, and F. F. Chehab
Effect of the Genetic Background on the Reproduction of Leptin-Deficient Obese Mice
Endocrinology, February 1, 1999; 140(2): 732 - 738.
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M. J. Cunningham, D. K. Clifton, and R. A. Steiner
Leptin's Actions on the Reproductive Axis: Perspectives and Mechanisms
Biol Reprod, February 1, 1999; 60(2): 216 - 222.
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F. M. GREGOIRE, C. M. SMAS, and H. S. SUL
Understanding Adipocyte Differentiation
Physiol Rev, July 1, 1998; 78(3): 783 - 809.
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O. Gavrilova, V. Barr, B. Marcus-Samuels, and M. Reitman
Hyperleptinemia of Pregnancy Associated with the Appearance of a Circulating Form of the Leptin Receptor
J. Biol. Chem., November 28, 1997; 272(48): 30546 - 30551.
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S. Bi, O. Gavrilova, D.-W. Gong, M. M. Mason, and M. Reitman
Identification of a Placental Enhancer for the Human Leptin Gene
J. Biol. Chem., November 28, 1997; 272(48): 30583 - 30588.
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B. Carlsson, C. Ankarberg, S. Rosberg, E. Norjavaara, K. Albertsson-Wikland, and L. M S Carlsson
Serum leptin concentrations in relation to pubertal development
Arch. Dis. Child., November 1, 1997; 77(5): 396 - 400.
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