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

Abstract

Hypothalamic melanocortins are among several neuropeptides strongly implicated in the control of food intake. Agonists for melanocortin 4 (MC-4) receptors such as -melanocyte-stimulating hormone ( -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 e ffect of diabetes on muscle uncoupling protein 3 (UCP-3), 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 n g / m l ) . 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 A g R P, 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. D i a b e t e s 49:244-252, 2000 H yperphagia (1,2) and altered fuel metabolism (3,4) are prominent features of uncontrolled diabetes. Although the pathogenesis of diabetic hyperphagia is incompletely understood, several observations suggest a key role for reduced signaling by insulin and leptin, hormones involved in the regulation of energy balance via their effects on the central nervous system (CNS) to regulate ...

The NPY/AgRP neuron and energy homeostasis

“…However, increases of AgRP mRNA in response to both fasting and genetic leptin deficiency are substantially greater than observed for NPY mRNA levels, whereas such differences are not apparent in STZ-diabetic rats. 72 Thus, although NPY and AgRP are both upregulated in the arcuate nucleus in response to the same stimuli, the magnitude of this response may differ. Distinct mechanisms may therefore govern the control of NPY and AgRP biosynthesis.…”

Uncoupling Proteins Prevent Glucose-Induced Neuronal Oxidative Stress and Programmed Cell Death

“…Recent investigations (13,21) have demonstrated that UCPs can prevent mitochondrial ROS formation. The different members of the UCP family have distinct tissue distributions (19,22,23). Tissue localization as well as regulation confer different roles for the family members.…”

“…For example, UCP1 is strictly restricted to brown adipose tissue, and its principal function is believed to be the generation of body heat (19,24). UCP3 tissue distribution is predominantly limited to skeletal muscle, whereas UCP2 expression is widespread in spleen, lung, stomach, white adipose tissue, and brain (23,25). Both UCPs regulate energy metabolism and weight regulation (19,20,26).…”

Neuroendocrine integration of nutritional signals on reproduction

“…Sub-populations of POMC neurons have been shown to co-express GABA and glutamate (Table 2). Perhaps not surprisingly, POMC/ CART neurons are regulated by insulin, leptin and ghrelin (Havel et al 2000, Cowley et al 2001, Balthasar et al 2004. Peripheral ghrelin peptide indirectly inhibits the activity of POMC/CART neurons in mice (Cowley et al 2003), but POMC/CART neurons may also be directly modulated by ghrelin-expressing neurons via synaptic communication (Guan et al 2008).…”