Effects of streptozotocin-induced diabetes and insulin treatment on the hypothalamic melanocortin system and muscle uncoupling protein 3 expression in rats

Peter J Havel, Tina M. Hahn, Dana K. Sindelar, Denis G. Baskin, Mary F. Dallman, David S. Weigle, Michael W. Schwartz

Research output: Contribution to journalArticle

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Abstract

Hypothalamic melanocortins are among several neuropeptides strongly implicated in the control of food intake. Agonists for melanocortin 4 (MC-4) receptors such as α-melanocyte-stimulating hormone (α-MSH), a product of proopiomelanocortin (POMC), reduce food intake, whereas hypothalamic agouti- related protein (AgRP) is a MC-4 receptor antagonist that increases food intake. To investigate whether reduced melanocortin signaling contributes to hyperphagia induced by uncontrolled diabetes, male Sprague-Dawley rats were studied 7 days after administration of streptozotocin (STZ) or vehicle. In addition, we wished to determine the effect of diabetes on muscle uncoupling protein 3 (UCP3), a potential regulator of muscle energy metabolism. STZ diabetic rats were markedly hyperglycemic (31.3 ± 1.0 mmol/l; P < 0.005) compared with nondiabetic controls (9.3 ± 0.2 mmol/l). Insulin treatment partially corrected the hyperglycemia (18.8 ± 2.5 mol/l; P < 0.005). Plasma leptin was markedly reduced in STZ diabetic rats (0.4 ± 0.1 ng/ml; P < 0.005) compared with controls (3.0 ± 0.4 ng/ml), an effect that was also partially reversed by insulin treatment (1.8 ± 0.3 ng/ml). Untreated diabetic rats were hyperphagic, consuming 40% more food (48 ± 1 g/day; P < 0.005) than controls (34 ± 1 g/day). Hyperphagia was prevented by insulin treatment (32 ± 2 g/day). In untreated diabetic rats, hypothalamic POMC mRNA expression (measured by in situ hybridization) was reduced by 80% (P < 0.005), whereas AgRP mRNA levels were increased by 60% (P < 0.01), suggesting a marked decrease of hypothalamic melanocortin signaling. The change in POMC, but not in AgRP, mRNA levels was partially reversed by insulin treatment. By comparison, the effects of diabetes to increase hypothalamic neuropeptide Y (NPY) expression and to decrease corticotropin-releasing hormone (CRH) expression were normalized by insulin treatment, whereas the expression of mRNA encoding the long form of the leptin receptor in the arcuate nucleus was unaltered by diabetes or insulin treatment. UCP-3 mRNA expression in gastrocnemius muscle from diabetic rats was increased fourfold (P < 0.005), and the increase was prevented by insulin treatment. The effect of uncontrolled diabetes to decrease POMC, while increasing AgRP gene expression, suggests that reduced hypothalamic melanocortin signaling, along with increased NPY and decreased CRH signaling, could contribute to diabetic hyperphagia. These responses in concert with increased muscle UCP-3 expression, may also contribute to the catabolic effects of uncontrolled diabetes on fuel metabolism in peripheral tissues.

Original languageEnglish (US)
Pages (from-to)244-252
Number of pages9
JournalDiabetes
Volume49
Issue number2
StatePublished - Feb 2000

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Melanocortins
Experimental Diabetes Mellitus
Muscle Proteins
Agouti-Related Protein
Pro-Opiomelanocortin
Insulin
Hyperphagia
Streptozocin
Messenger RNA
Receptor, Melanocortin, Type 4
Eating
Neuropeptide Y
Corticotropin-Releasing Hormone
Melanocyte-Stimulating Hormones
Leptin Receptors
Muscles
Arcuate Nucleus of Hypothalamus
Leptin
Uncoupling Protein 3
Neuropeptides

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Havel, P. J., Hahn, T. M., Sindelar, D. K., Baskin, D. G., Dallman, M. F., Weigle, D. S., & Schwartz, M. W. (2000). Effects of streptozotocin-induced diabetes and insulin treatment on the hypothalamic melanocortin system and muscle uncoupling protein 3 expression in rats. Diabetes, 49(2), 244-252.

Effects of streptozotocin-induced diabetes and insulin treatment on the hypothalamic melanocortin system and muscle uncoupling protein 3 expression in rats. / Havel, Peter J; Hahn, Tina M.; Sindelar, Dana K.; Baskin, Denis G.; Dallman, Mary F.; Weigle, David S.; Schwartz, Michael W.

In: Diabetes, Vol. 49, No. 2, 02.2000, p. 244-252.

Research output: Contribution to journalArticle

Havel, PJ, Hahn, TM, Sindelar, DK, Baskin, DG, Dallman, MF, Weigle, DS & Schwartz, MW 2000, 'Effects of streptozotocin-induced diabetes and insulin treatment on the hypothalamic melanocortin system and muscle uncoupling protein 3 expression in rats', Diabetes, vol. 49, no. 2, pp. 244-252.
Havel, Peter J ; Hahn, Tina M. ; Sindelar, Dana K. ; Baskin, Denis G. ; Dallman, Mary F. ; Weigle, David S. ; Schwartz, Michael W. / Effects of streptozotocin-induced diabetes and insulin treatment on the hypothalamic melanocortin system and muscle uncoupling protein 3 expression in rats. In: Diabetes. 2000 ; Vol. 49, No. 2. pp. 244-252.
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