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: 2.98). 01/2007; 89(5):687-91. DOI: 10.1016/j.physbeh.2006.08.008
Source: PubMed


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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    • "Besides increased plasma glucose levels, obese/insulin-resistant subjects usually present a compensatory hyperinsulinemia, which may lead to plenty of secondary complications, such as cancer, cardiovascular diseases, and benign prostatic hyperplasia (Contreras et al., 2010; Heuson et al., 1972; Heuson and Legros , 1972; Vikram et al., 2010). At the level of the CNS, insulin regulates food intake, body weight, reproduction, and adiposity along with other peripheral functions, such as gastric motility (Blake and Smith, 2012; Brown et al., 2006; Brü ning et al., 2000; Koch et al., 2008). As we did not detect changes in local bronchial reactivity, tissue remodeling, and inflammatory status in DIO mice, we hypothesized that elevated levels of insulin in the CNS lead to an increased cholinergic output into the airways causing an exacerbated bronchoconstriction in these animals. "
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    ABSTRACT: Obesity is a major risk factor for asthma, which is characterized by airway hyperreactivity (AHR). In obesity-associated asthma, AHR may be regulated by non-TH2 mechanisms. We hypothesized that airway reactivity is regulated by insulin in the CNS, and that the high levels of insulin associated with obesity contribute to AHR. We found that intracerebroventricular (ICV)-injected insulin increases airway reactivity in wild-type, but not in vesicle acetylcholine transporter knockdown (VAChT KD(HOM-/-)), mice. Either neutralization of central insulin or inhibition of extracellular signal-regulated kinases (ERK) normalized airway reactivity in hyperinsulinemic obese mice. These effects were mediated by insulin in cholinergic nerves located at the dorsal motor nucleus of the vagus (DMV) and nucleus ambiguus (NA), which convey parasympathetic outflow to the lungs. We propose that increased insulin-induced activation of ERK in parasympathetic pre-ganglionic nerves contributes to AHR in obese mice, suggesting a drug-treatable link between obesity and asthma. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 04/2015; 11(6). DOI:10.1016/j.celrep.2015.04.012 · 8.36 Impact Factor
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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; 66(5). DOI:10.1016/j.yhbeh.2014.08.015 · 4.63 Impact Factor
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    • "Since neither WPI nor increasing the P/C ratio influenced plasma corticosterone levels, adipose expression of 11β-HSD1 or hypothalamic expression of GCCR in HFD fed mice, it is possible that WPI may have affected other central mechanisms mediating stress responses not investigated in this study [48]–[50] either independently or in combination with key mechanisms regulating energy balance. Given that leptin decreases meal size and number [51]–[53], and WPI reduced the HFD-induced increase in plasma leptin levels, it's possible that WPI-derived bioactives could have specifically influenced circadian rhythm of leptin production and/or action within the neuroendocrine state of HFD-fed mice in a socially isolated environment. Additionally, the reduction in plasma amino acids associated with WPI intake (see below), could also have acted as a possible central trigger to increase energy intake in WPI groups compared to HFD control in the single house environment. "
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    ABSTRACT: Macronutrient quality and composition are important determinants of energy balance and the gut microbiota. Here, we investigated how changes to protein quality (casein versus whey protein isolate; WPI) and the protein to carbohydrate (P/C) ratio within a high fat diet (HFD) impacts on these parameters. Mice were fed a low fat diet (10% kJ) or a high fat diet (HFD; 45% kJ) for 21 weeks with either casein (20% kJ, HFD) or WPI at 20%, 30% or 40% kJ. In comparison to casein, WPI at a similar energy content normalised energy intake, increased lean mass and caused a trend towards a reduction in fat mass (P = 0.08), but the protein challenge did not alter oxygen consumption or locomotor activity. WPI reduced HFD-induced plasma leptin and liver triacylglycerol, and partially attenuated the reduction in adipose FASN mRNA in HFD-fed mice. High throughput sequence-based analysis of faecal microbial populations revealed microbiota in the HFD-20% WPI group clustering closely with HFD controls, although WPI specifically increased Lactobacillaceae/Lactobacillus and decreased Clostridiaceae/Clostridium in HFD-fed mice. There was no effect of increasing the P/C ratio on energy intake, but the highest ratio reduced HFD-induced weight gain, fat mass and plasma triacylglycerol, non-esterified fatty acids, glucose and leptin levels, while it increased lean mass and oxygen consumption. Similar effects were observed on adipose mRNA expression, where the highest ratio reduced HFD-associated expression of UCP-2, TNFα and CD68 and increased the diet-associated expression of β3-AR, LPL, IR, IRS-1 and GLUT4. The P/C ratio also impacted on gut microbiota, with populations in the 30/40% WPI groups clustering together and away from the 20% WPI group. Taken together, our data show that increasing the P/C ratio has a dramatic effect on energy balance and the composition of gut microbiota, which is distinct from that caused by changes to protein quality.
    PLoS ONE 02/2014; 9(2):e88904. DOI:10.1371/journal.pone.0088904 · 3.23 Impact Factor
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