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

Abstract

Jayaram B, Pan W, Wang Y, Hsuchou H, Mace A, CornelissenGuillaume GG, Mishra PK, Koza RA, Kastin AJ. Astrocytic leptin receptor knockout mice show partial rescue of leptin resistance in diet-induced obesity. J Appl Physiol 114: 734 -741, 2013. First published January 17, 2013 doi:10.1152/japplphysiol.01499.2012.-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 leptin receptor (ObR) signaling. ALKO mice and wild-type (WT) littermate controls were studied at different stages of DIO with measurement of body wt, percent fat, metabolic activity, and biochemical parameters. When fed regular chow, the ALKO mice had similar body wt, 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 in UCP1 mRNA. Thus, ALKO mice did not show the worsening of obesity that occurs with normal WT mice and the neuronal ObR mutation that results in morbid obesity. The findings are consistent with a competing, counterregulatory model between neuronal and astrocytic leptin signaling. astrocytes; ALKO; metabolic phenotype LEPTIN IS A SO-CALLED LEAN HORMONE that suppresses food intake and curtails weight gain. Predominantly secreted by subcutaneous adipose tissue, this 16-kDa polypeptide crosses the blood-brain barrier (BBB) to reach the hypothalamus and regulate feeding. Both neurons and astrocytes express leptin receptors (ObRs) (11), but the functions of astrocytic leptin signaling in astrocyte-neuron interactions are not clear. When mice receive an intracerebroventricular injection of fluorocitrate, an inhibitor of astrocytic metabolic activity, there is an increase in the amount of leptin transported to the neurons and phosphorylation of Signal Transducer and Activator of Transcription (pSTAT3) in the hypothalamus, indicating greater leptin signaling (23). This suggests that astrocytic and neuronal leptin signaling compete with each other.The effects of leptin are mediated by ObR isoforms generated by alternative splicing mainly in the regions encoding the cytoplasmic domain. ObRb is the longest receptor isoform that is able to induce pSTAT3 activation; in the absence of ObRb, db/db mice show hyperphagia and severe diabesity. They have hyperleptinemia, hyperinsulinemia, hypercorticosteronemia, infertility, and cold intolerance. Neuronal-specific mutation of ObR impairs hypothalamic functions and mimics the obese phenotype observed in db/db mice (4, 5, 15). The metabolic phenotype of astrocytic ObR mut...

Effects of diet-induced obesity and voluntary exercise in a tauopathy mouse model: Implications of persistent hyperleptinemia and enhanced astrocytic leptin receptor expression

“…Interestingly, ALKO showed less hyperleptinemia and GFAP expression than WT mice when HCD was supplied, although the differences between ALKO and WT mice were not seen when SD was supplied (Jayaram et al, 2013). They speculated that in the case of prolonged HCD, astrocytic LepRs became highly reactive to circulating concentrations of leptin, followed by astroglial activation and proinflammatory cytokine secretion, which eventually led to neuroinflammation.…”

“…They speculated that in the case of prolonged HCD, astrocytic LepRs became highly reactive to circulating concentrations of leptin, followed by astroglial activation and proinflammatory cytokine secretion, which eventually led to neuroinflammation. Neuroinflammation reduces sensitivity of neurons to leptin (leptin resistance), enhancing hyperleptinemia even more (Jayaram et al, 2013). This speculation is based on a series of pathological events in the hypothalamus that explain the impaired leptin signaling.…”

Astrocytes: new targets of melanocortin 4 receptor actions

“…A recent report shows that neonatal overnutrition increased body weight and leptin, affecting glial cells as GFAP, glucose, and glutamate transporter expression were increased in hypothalamus, further suggesting that physiological changes in metabolic state can modulate astrocyte functions (Fuente-Martin et al 2012). Moreover, astrocyte leptin receptor knockout mice showed less severe obesity than wild-type mice (Jayaram et al 2013). While much remains to be understood about the astrocyte role in energy homeostasis, it seems clear that these cells are key players in the CNS response to obesity.…”

Hypothalamic and brainstem neuronal circuits controlling homeostatic energy balance

“…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).…”