Obesity is associated with altered metabolic and reproductive activity in the mare: effects of metformin on insulin sensitivity and reproductive cyclicity*
M. M. Vick A , D. R. Sessions A , B. A. Murphy A , E. L. Kennedy A , S. E. Reedy A and B. P. Fitzgerald A BA Department of Veterinary Science, Maxwell Gluck Equine Research Center, University of Kentucky, Lexington, KY 40546, USA.
B Corresponding author. Email: bfitz@uky.edu
Reproduction, Fertility and Development 18(6) 609-617 https://doi.org/10.1071/RD06016
Submitted: 28 February 2006 Accepted: 9 April 2006 Published: 9 June 2006
Abstract
In mares, obesity is associated with continuous reproductive activity during the non-breeding season. To investigate the effect of obesity and associated alterations in metabolic parameters on the oestrous cycle, two related studies were conducted. In Experiment 1, obese (body condition score > 7) mares were fed ad libitum or were moderately feed restricted during the late summer and autumn months. Feed restriction did not alter the proportion of mares entering seasonal anoestrus. However, obese mares exhibited a significantly longer duration of the oestrous cycle, significant increases in circulating concentrations of leptin and insulin, and decreased insulin sensitivity and concentrations of thyroxine compared with feed-restricted mares throughout the experiment. Experiment 2 was designed to investigate the effects of administration of the insulin-sensitising drug metformin hydrochloride on insulin sensitivity and the characteristics of the oestrous cycle in obese mares. In a dose–response trial, metformin increased insulin sensitivity after 30 days following administration of 3 g day–1, but not 6 or 9 g day–1, compared with controls receiving vehicle only. However, there were no differences in insulin sensitivity or oestrous cycle characteristics between control and metformin-treated groups when the 3 g day–1 dose was tested for a longer period of 2 months. These results demonstrate that obesity is associated with aberrations in the oestrous cycle and perturbations in several markers of metabolic status. The results also indicate that metformin is not an effective long-term monotherapy for increasing insulin sensitivity in horses at the doses tested. Additional studies are needed to examine possible effects of increasing insulin sensitivity on reproductive activity in obese mares.
Extra keywords: horse, insulin resistance, reproduction.
Acknowledgments
The research reported in this article (No. 04-14-043) is published in connection with a project of the Kentucky Agricultural Experiment Station and is supported by funding from the Kentucky Equine Research Foundation. The authors acknowledge the contribution of Brenda White from the Veterinary Science Department at the University of Kentucky (Lexington, KY, USA) to this body of work and would like to thank the farm crew of the University of Kentucky Main Chance farm who provided invaluable assistance during data collection. The authors also acknowledge Scott McClintock from the Statistics Department at the University of Kentucky for his assistance with statistical analysis.
Ahima, R. S. , Saper, C. B. , Flier, J. S. , and Elmquist, J. K. (2000). Leptin regulation of neuroendocrine systems. Front. Neuroendocrinol. 21, 263–307.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
McCue, P. M. , and Squires, E. L. (2002). Persistent anovulatory follicles in the mare. Theriogenology 58, 541–543.
| Crossref | GoogleScholarGoogle Scholar |
McManus, C. J. , and Fitzgerald, B. P. (1999). Daily administration of clenbuterol decreases leptin concentrations but does not influence the timing of anestrus in the mare. Biol. Reprod. 60(Suppl. 1), 187.
McManus, C. J. , and Fitzgerald, B. P. (2003). Effect of daily clenbuterol and exogenous melatonin treatment on body fat, serum leptin and the expression of seasonal anestrus in the mare. Anim. Reprod. Sci. 76, 217–230.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
McMurtry, J. P. , Plavnik, I. , Rosebrough, R. W. , Steele, N. C. , and Proudman, J. A. (1988). Effect of early feed restriction in male broiler chicks on plasma metabolic hormones during feed restriction and accelerated growth. Comp. Biochem. Physiol. A 91, 67–70.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Nagy, P. , Guillaume, D. , and Daels, P. (2000). Seasonality in mares. Anim. Reprod. Sci. 60–61, 245–262.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Ortiz, R. M. , MacKenzie, D. S. , and Worthy, G. A. (2000). Thyroid hormone concentrations in captive and free-ranging West Indian manatees (Trichechus manatus). J. Exp. Biol. 203, 3631–3637.
| PubMed |
Ortiz, R. M. , Wade, C. E. , and Ortiz, C. L. (2001). Effects of prolonged fasting on plasma cortisol and TH in postweaned northern elephant seal pups. Am. J. Physiol. Regul. Integr. Comp. Physiol. 280, R790–R795.
| PubMed |
Panidis, D. , Macut, D. , Farmakiotis, D. , Rousso, D. , Kourtis, A. , Katsikis, I. , Spanos, N. , Petakov, M. , Bjekic, J. , and Damjanovic, S. (2006). Indices of insulin sensitivity, beta cell function and serum proinsulin levels in the polycystic ovary syndrome. Eur. J. Obstet. Gynecol. Reprod. Biol. ,in press.
Powell, D. M. , Lawrence, L. M. , Fitzgerald, B. P. , Danielsen, K. , Parker, A. , Siciliano, P. , and Crum, A. (2000). Effect of short-term feed restriction and calorie source on hormonal and metabolic responses in geldings receiving a small meal. J. Anim. Sci. 78, 3107–3113.
| PubMed |
Powell, D. M. , Reedy, S. E. , Sessions, D. R. , and Fitzgerald, B. P. (2002). Effect of short-term exercise training on insulin sensitivity in obese and lean mares. Equine Vet. J. Suppl. 34, 81–84.
| PubMed |
Ralston, S. L. (1986). Feeding behavior. Vet. Clin. North Am. Equine Pract. 2, 609–621.
| PubMed |
Riis, A. L. , Gravholt, C. H. , Djurhuus, C. B. , Norrelund, H. , Jorgensen, J. O. , Weeke, J. , and Moller, N. (2002). Elevated regional lipolysis in hyperthyroidism. J. Clin. Endocrinol. Metab. 87, 4747–4753.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Robinson, R. S. , Hunter, M. G. , and Mann, G. E. (2005). Supra-basal progesterone concentrations during the follicular phase are associated with development of cystic follicles in dairy cows. Vet. J. ,in press.
Sessions, D. R. , Reedy, S. E. , Vick, M. M. , Murphy, B. A. , and Fitzgerald, B. P. (2004). Development of a model for inducing transient insulin resistance in the mare: preliminary implications regarding the estrous cycle. J. Anim. Sci. 82, 2321–2328.
| PubMed |
Silvia, P. J. , Meyer, S. L. , and Fitzgerald, B. P. (1995). Pulsatile gonadotropin secretion determined by frequent sampling from the intercavernous sinus of the mare: possible modulatory role of progesterone during luteolysis. Biol. Reprod. 53, 438–446.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Sirotkin, A. V. , Mlyncek, M. , Kotwica, J. , Makarevich, A. V. , Florkovicova, I. , and Hetenyi, L. (2005). Leptin directly controls secretory activity of human ovarian granulosa cells: possible inter-relationship with the IGF/IGFBP system. Horm. Res. 64, 198–202.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Song, S. , Andrikopoulos, S. , Filippis, C. , Thorburn, A. W. , Khan, D. , and Proietto, J. (2001). Mechanism of fat-induced hepatic gluconeogenesis: effect of metformin. Am. J. Physiol. Endocrinol. Metab. 281, E275–E282.
| PubMed |
Sticker, L. , Thompson, D. , Bunting, L. , Fenandez, J. , DePew, C. , and Nadal, M. (1995a). Feed deprivation of mares: plasma metabolite and hormonal concentrations and responses to exercise. J. Anim. Sci. 73, 3696–3704.
| PubMed |
Sticker, L. , Thompson, D. , Fernandez, J. , Bunting, L. , and DePew, C. L. (1995b). Dietary protein and(or) energy restriction in mares: plasma growth hormone, IGF-I, prolactin, cortisol, and thyroid hormone responses to feeding, glucose, and epinephrine. J. Anim. Sci. 73, 1424–1432.
| PubMed |
Suwannachot, P. , Verkleij, C. B. , Kocsis, S. , Enzerink, E. , and Everts, M. E. (2000). Prolonged food restriction and mild exercise in Shetland ponies: effects on weight gain, thyroid hormone concentrations and muscle Na(+),K(+)-ATPase. J. Endocrinol. 167, 321–329.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Veiga-Lopez, A. , Gonzalez-Bulnes, A. , Tresguerres, J. A. , Dominguez, V. , Ariznavarreta, C. , and Cocero, M. J. (2006). Causes, characteristics and consequences of anovulatory follicles in superovulated sheep. Domest. Anim. Endocrinol. 30, 76–87.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Vrbikova, J. , Hill, M. , Starka, L. , Cibula, D. , Bendlova, B. , Vondra, K. , Sulcova, J. , and Snajderova, M. (2001). The effects of long-term metformin treatment on adrenal and ovarian steroidogenesis in women with polycystic ovary syndrome. Eur. J. Endocrinol. 144, 619–628.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Wiltbank, M. C. , Gumen, A. , and Sartori, R. (2002). Physiological classification of anovulatory conditions in cattle. Theriogenology 57, 21–52.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Zieba, D. A. , Amstalden, M. , and Williams, G. L. (2005). Regulatory roles of leptin in reproduction and metabolism: a comparative review. Domest. Anim. Endocrinol. 29, 166–185.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
* M. M. Vick and B. P. Fitzgerald contributed equally to the body of work presented herein.
