Astrocytic leptin-receptor knockout mice show partial rescue of leptin resistance in diet-induced obesity

1Pennsington Biomedical Research Center.
Journal of Applied Physiology (Impact Factor: 3.06). 01/2013; 114(6). DOI: 10.1152/japplphysiol.01499.2012
Source: PubMed


To determine how astrocytic leptin signaling regulates the physiological response of mice to diet-induced obesity (DIO), we performed metabolic analyses and hypothalamic leptin signaling assays on astrocytic leptin receptor knockout (ALKO) mice in which astrocytes lack functional ObR signaling. ALKO mice and wildtype (WT) littermate controls were studied at different stages of DIO, with measurement of body weight, percent fat, metabolic activity, and biochemical parameters. When fed with regular chow, the ALKO mice had similar body weight, percent fat, food intake, heat dissipation, respiratory exchange ratio, and activity as their WT littermates. There was no change in blood concentrations of triglyceride, soluble leptin receptor (sObR), mRNA for leptin and uncoupling protein 1 (UCP1) in adipose tissue, and insulin sensitivity. Unexpectedly, in response to a high fat diet the ALKO mice had attenuated hyperleptinemia and sObR, a lower level of leptin mRNA in subcutaneous fat, and a paradoxical increase of UCP1 mRNA. Thus, ALKO mice did not show the worsening of obesity that occurs with normal WT mice as well as with the neuronal ObR mutation resulting in morbid obesity. The findings are consistent with a competing, counter-regulatory model between neuronal and astrocytic leptin signaling.

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Available from: Weihong Pan, Jul 26, 2015
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    • "Recently, Jayaram et al. that reported that DIO did not increase GFAP expression in astrocyte-specific LepR knockout mice; rather, it reduced [10]. Although they did not mention the isoform of astrocytic LepR, our study showed that LepRs, not LepRl, was expressed in astrocytes. "
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    ABSTRACT: Accumulating evidence indicates that obesity is an independent risk factor for developing Alzheimer disease (AD). Recent studies have shown that diet-induced obesity (DIO) enhances AD-related pathologies in transgenic mouse models of the disease. DIO increases amyloid β (Aβ) deposition in amyloidogenic transgenic mice and enhances tau phosphorylation in tau transgenic mice. However, it remains unclear whether DIO also enhances AD-related pathological processes in wild-type (WT) mice. In this study, we examined the effects of DIO on Aβ and tau pathology in WT mice using immunohistochemistry. In addition, we evaluated the protective effect of voluntary exercise on the DIO-induced pathological changes. DIO caused tau phosphorylation and astroglial activation in the hippocampus in WT mice. Interestingly, these changes were associated with enhanced astrocytic leptin receptor (LepR) expression and mild microgliosis, but not Aβ accumulation. Although phosphorylated tau staining was only observed in the hippocampus, astrogliosis and microgliosis were present in both the amygdala and hippocampus. However, no apparent neuronal loss was observed. Voluntary exercise prevented these DIO-induced pathological changes. Our results demonstrate for the first time that DIO causes tau phosphorylation and that astrocytic LepR might be involved in the pathological process in WT mouse hippocampus. Our findings also suggest that physical exercise is a promising strategy for the prevention of AD in patients with obesity.
    Neuroscience Letters 04/2014; 571. DOI:10.1016/j.neulet.2014.04.028 · 2.03 Impact Factor
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    • "It has also been reported that DIO mice exhibit increased expression of functional astrocytic LEPR in the hypothalamic region, an effect that may play a role in the development of leptin resistance (Hsuchou et al. 2009a). Indeed, loss of astrocytic Lepr under HFD conditions provides partial protection against developing disturbances in neuronal leptin signaling (Jayaram et al. 2013). Obesity and lipid overload induce chronic low-grade inflammation in the hypothalamus (Thaler et al. 2010). "
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    ABSTRACT: Alterations in adequate energy balance maintenance results in serious metabolic disturbances such as obesity. In mammals, this complex process is orchestrated by multiple and distributed neuronal circuits. Hypothalamic and brainstem neurocircuitries are critically implicated in the sensing of circulating and local factors informing about the energy status of the organism. The integration of these signals culminates in the generation of specific and coordinated physiological responses aimed to regulate energy balance through the modulation of appetite and energy expenditure. In this article we review current knowledge on the homeostatic regulation of energy balance, emphasizing recent advances in mouse genetics, electrophysioly and optogenetic techniques that have greatly contributed to improve our understanding of this central process.
    Journal of Endocrinology 11/2013; 220(2). DOI:10.1530/JOE-13-0398 · 3.72 Impact Factor
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    • "), mouse models of obesity seldom show signs of sleep apnea, even though astrogliosis and neuroinflammation may be evident in certain CNS regions (Hsuchou et al. 2009; Pan et al. 2008, 2012b; Jayaram et al. 2013). There are few non-human studies testing the interactions between sleep and changes in neurobehavior. "
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    ABSTRACT: Excessive obesity correlates with hypersomnolence and impaired cognitive function, presumably induced by metabolic factors and cytokines. Production of the adipokine leptin correlates with the amount of adiposity, and leptin has been shown to promote sleep. To determine whether leptin plays a major role in the hypersomnolence of obesity, we measured sleep architecture in pan-leptin receptor knockout (POKO) mice that do not respond to leptin because of the production of a mutant, non-signaling receptor. The obese POKO mice had more non-rapid eye movement (NREM) sleep and less waking time than their littermate controls. This was mainly seen during the light span, although increased bouts of rapid eye movement sleep were also seen in the dark span. The increase of NREM sleep correlated with the extent of obesity. The POKO mice also had decreased locomotor activity and more immobility in the open field test, but there was no increase of forced immobility nor reduction of sucrose intake as would be seen in depression. The increased NREM sleep and reduced locomotor activity in the POKO mice suggest that it was obesity, rather than leptin signaling, that played a predominant role in altering sleep architecture and activity.
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