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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    • "The pleiotrophy of adipokines allows mice without astrocytic LepR [21] to have relatively normal metabolic and neurobehavioral phenotypes during most of adulthood in the unchallenged state. However, there are differences in the metabolic profile when mice are fed with a high-fat diet [26] [81]. Further, unpublished work by Yi He and others in the lab indicates that the compensatory changes in normal metabolic phenotype are lost when the astrocytic LepR knockout (ALKO) mice reach an older age (8 months). "
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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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    • "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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