Intraventricular insulin and leptin reduce food intake and body weight in C57BL/6J mice.

Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio 45237, USA.
Physiology & Behavior (Impact Factor: 3.03). 01/2007; 89(5):687-91. DOI: 10.1016/j.physbeh.2006.08.008
Source: PubMed

ABSTRACT As the incidence of obesity continues to increase, adequate animal models acquire increased importance for the investigation of energy homeostatic mechanisms. Understanding the central mechanism of action of the adiposity hormones, insulin and leptin, has become particularly important as researchers examine ways to treat or prevent obesity. Although the intra-3rd-ventricular (i3vt) administration of insulin reduces food intake in several species, its effects on food intake and body weight have not been previously been assessed in mice. Male C57BL/6J mice were administered insulin i3vt (0.05, 0.1 or 0.4 microU) or leptin i3vt (5 microg/1 microl) as a positive control. As it occurs in other species, i3vt insulin dose-dependently reduced 24-h food intake and body weight, and increased hypothalamic proopiomelanocortin (POMC) mRNA. Hence, genetic manipulations that influence brain insulin sensitivity in mice can now more easily be integrated with the broader literature on energy homeostasis.

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    • "Indeed, insulin and leptin are major adiposity signals (Woods and Seeley, 2000), e.g., they are directly related to body fat and they regulate food intake and energy homeostasis by acting on the central nervous system (CNS) (Schwartz et al., 1999; Woods et al., 1998). Thus, the binding of these two hormones to their receptors in the hypothalamus reduces food intake, and increases energy expenditure and body weight loss (Air et al., 2002; Brown et al., 2006; McGowan et al., 1992, 1990; Seeley et al., 1996). The results of correlation between body weight and plasma levels of these hormones are in agreement with the abovementioned studies. "
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    ABSTRACT: Studies have shown a gradual reduction of sleep time in the general population, accompanied by increased food intake, representing a risk for developing obesity, type II diabetes and cardiovascular disease. Rats subjected to paradoxical sleep deprivation (PSD) exhibit feeding and metabolic alterations, both of which are regulated by the communication between peripheral signals and the hypothalamus. This study aimed to investigate the daily change of 96 h of PSD-induced food intake, body weight, blood glucose, plasma insulin and leptin concentrations and the expression of their receptors in the hypothalamus of Wistar rats. Food intake was assessed during the light and dark phases and was progressively increased in sleep-deprived animals, during the light phase. PSD produced body weight loss, particularly on the first day, and decreased plasma insulin and leptin levels, without change in blood glucose levels. Reduced leptin levels were compensated by increased expression of leptin receptors in the hypothalamus, whereas no compensations occurred in insulin receptors. The present results on body weight loss and increased food intake replicate previous studies from our group. The fact that reduced insulin levels did not lead to compensatory changes in hypothalamic insulin receptors, suggests that this hormone may be, at least in part, responsible for PSD-induced dysregulation in energy metabolism.
    Hormones and Behavior 10/2014; DOI:10.1016/j.yhbeh.2014.08.015 · 4.51 Impact Factor
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    • "Having established that CNTF regulates gene expression in our cell model, we then treated the neurons with insulin and found that it also increased levels of c-fos and POMC. These results provide evidence that the mHypoA-POMC/GFP-1 neurons respond appropriately to insulin, as several groups have shown that insulin regulates transcriptional events within POMC neurons in vivo to induce expression of the Pomc gene (Brown et al. 2006, Kitamura et al. 2006, Plum et al. 2006a). Further studies will determine whether this effect is due to transcriptional regulation at the level of the promoter or to changes in RNA stability. "
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    ABSTRACT: Proopiomelanocortin (POMC) neurons play a central role in the maintenance of whole body energy homeostasis. This balance requires proper regulation of POMC neurons by metabolic hormones, such as insulin. However, the heterogeneous cellular population of the intact hypothalamus presents challenges for examining the molecular mechanisms underlying the potent anorexigenic effects of POMC neurons, and there is currently a complete lack of mature POMC neuronal cell models for study. To this end, we have generated novel, immortalized, adult-derived POMC-expressing/alpha-melanocyte stimulating hormone (αMSH)-secreting cell models, mHypoA-POMC/GFP lines 1-4, representing the fluorescence-activated cell-sorted POMC population from primary POMC-eGFP mouse hypothalamus. The presence of POMC mRNA in these cell lines was confirmed, and α-MSH was detected via immunofluorescence. α-MSH secretion in the mHypoA-POMC/GFP-1 was found to increase in response to 10 ng/ml ciliary neurotrophic factor (CNTF) or 10 nM insulin as determined by enzyme immunoassay. Further experiments using the mHypoA-POMC/GFP-1 cell line revealed that 10 ng/ml CNTF increases POMC mRNA at 1 and 2 hours after treatment, whereas insulin elicited an increase in POMC and decreases in insulin receptor (IR) mRNA levels at 4 h. Furthermore, the activation of IR-mediated downstream second messengers was examined by Western blot analysis, following the induction of cellular insulin resistance, which resulted in a loss of insulin-mediated regulation of POMC and IR mRNAs. The development of these immortalized neurons will be invaluable for the elucidation of the cellular and molecular mechanisms that underlie POMC neuronal function under normal and perturbed physiological conditions.
    Journal of Endocrinology 10/2013; DOI:10.1530/JOE-13-0334 · 3.59 Impact Factor
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    • "As with leptin, the circulating levels of insulin are positively correlated with adiposity and body weight (Woods and Seeley, 2000). Delivery of insulin to the central nervous system decreases food intake and body weight in mice (Brown et al., 2006) and men (Hallschmid et al., 2004). "
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    ABSTRACT: Because of the substantial energy demands of reproduction, the brain must temper the fertility of individuals to match nutritional availability. Under-nutrition is associated with infertility in humans and animals. The brain uses adipose- and gut-derived hormones, such as leptin, insulin and ghrelin, to modulate the activity of the GnRH neuronal network that drives reproduction. It is becoming clear that there are both direct and indirect pathways acting on GnRH neurones. A PubMed search was performed using keywords associated with neuropeptides and metabolic hormones that are associated with reproductive and energy balance axes. Evidence that neurones which produce galanin, galanin-like peptide, kisspeptin, alpha-melanocyte-stimulating hormone, neuropeptide Y and oxytocin convey metabolic information to the reproductive axis is presented. The extent to which these neurones express receptors for metabolic hormones is variable but interactions between them allows for complex intermingling of information. Available metabolic fuels modulate hormone input to these neurones, leading in turn to altered GnRH release and appropriate drive to the gonads. The consequent change in sex steroid production is likely to contribute to co-ordination of the network. We hypothesize that the absence of an estrogenic milieu during anovulation compared with presence of estradiol during follicular maturation is important for the regulation of most of the neuropeptides. An improved understanding of the normal responses to energy deprivation may also help to identify novel therapeutic targets for infertility that often accompanies metabolic disorders, such as diabetes, obesity and polycystic ovary syndrome.
    Human Reproduction Update 03/2012; 18(3):313-32. DOI:10.1093/humupd/dms004 · 8.66 Impact Factor
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