Endothelial leptin receptor mutation provides partial resistance to diet-induced obesity

Pan, Weihong; Hsuchou, Hung; Cornelissen-Guillaume, Germaine G; Jayaram, Bhavvani; Wang, Yuping; Tu, Hong; Halberg, Franz; Wu, Xiaojun; Chua, Streamson C.; Kastin, Abba J.

doi:10.1152/japplphysiol.00590.2011

Cited by 15 publications

(26 citation statements)

References 30 publications

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“…The results are in major contrast to those we recently reported for endothelial leptin receptor knockout (ELKO) mice (18). ELKO mice have an endothelial-specific mutation of ObR resulting from crossing Tie2-cre heterozygote mice with ObR-floxed homozygote mice with loxP sites flanking exon 17; the resulting F1 heterozygote mice contain both cre and floxed genes and were further crossed with ObR-floxed homozygotes.…”

Section: Discussioncontrasting

confidence: 99%

“…The ALKO mice show hyperleptinemia in the absence of obesity at baseline, though the elevation is much less than the 15-fold increase observed in the ELKO mice. However, there was a higher basal level in the ALKO mice on an FVB background than in the ELKO mice on a C57 background, probably related to age and strain differences (18).…”

Section: Discussionmentioning

confidence: 79%

“…Apparently, the ELKO mutation is associated with partial resistance to DIO. This points to a facilitatory role of endothelial leptin signaling in obesity development (18).…”

Section: Discussionmentioning

confidence: 89%

“…The effects of overnight fasting were also tested. V O2, V CO2, RER, heat dissipation, activity, and feeding were sampled every 18 min, as described previously (18).…”

Section: Methodsmentioning

confidence: 99%

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

Jayaram

Pan

Wang

et al. 2013

Journal of Applied Physiology

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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...

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 79%

“…Apparently, the ELKO mutation is associated with partial resistance to DIO. This points to a facilitatory role of endothelial leptin signaling in obesity development (18).…”

Section: Discussionmentioning

confidence: 89%

“…The effects of overnight fasting were also tested. V O2, V CO2, RER, heat dissipation, activity, and feeding were sampled every 18 min, as described previously (18).…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

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

Jayaram

Pan

Wang

et al. 2013

Journal of Applied Physiology

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“…The better preserved biochemical profile in the ALKO-Δ17 mice suggests that astrocytic LepR signaling worsens obesity, a role counter to that of neuronal LepR (Jayaram et al, 2013). The results differ from the diabesity of neuronal LepR knockout mice ( Kowalski et al, 2001; McMinn et al, 2005), but are more congruous with the endothelial LepR mutant mice that also produce a mutant, membrane-bound LepR in endothelia and show partial resistance to DIO (Pan et al, 2012a). …”

Section: Discussionmentioning

confidence: 59%

Role of Astrocytes in Leptin Signaling

Wang

Hsuchou

et al. 2015

J Mol Neurosci

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To test the hypothesis that astrocytic leptin signaling induces an overall potentiation of the neuronal response to leptin, we generated a new line of astrocyte-specific leptin receptor knockout (ALKO-Δ1) mice in which no leptin receptor is expressed in astrocytes. Corresponding to cell-specific cre-recombinase expression in hypothalamic astrocytes but not neurons, this new strain of ALKO mice had attenuated pSTAT3 signaling in the arcuate nucleus of the hypothalamus 30 min after intracerebroventricular delivery of leptin. In response to high fat diet for two months, the ALKO mice showed a greater increase of percent fat and blood leptin concentration. This coincided with a mild reactive gliosis in the hypothalamus. Overall, the absence of leptin receptors in astrocytes attenuated hypothalamic pSTAT3 signaling, induced a mild reactive morphology, and promoted the development of diet-induced obesity. We conclude that leptin signaling in astrocytes is essential for the homeostasis of neuroendocrine regulation in obesity.

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Endothelial cell leptin receptor mutant mice have hyperleptinemia and reduced tissue uptake

Hsuchou

Jayaram

Kastin

et al. 2013

Journal Cellular Physiology

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Hyperleptinemia is usually associated with obesity and leptin resistance. Endothelial cell leptin receptor knockout (ELKO) mice without a signaling membrane-bound leptin receptor in endothelia, however, have profound hyperleptinemia without signs of leptin resistance. Leptin mRNA in adipose tissue was unchanged. To test the hypothesis that the ELKO mutation results in delayed degradation and slowed excretion, we determined the kinetics of leptin transfer in groups of ELKO and wildtype mice after intravenous bolus injection of 125I-leptin and the reference substance 131I-albumin. The degradation pattern of 125I-leptin in serum and brain homogenates at different time points between 10-60 min was measured by HPLC and acid precipitation. Although ELKO mice had reduced uptake of 125I-leptin uptake by the brain and several peripheral organs, leptin was more stable in blood and tissue. There was no change in the rate of renal excretion. ELISA showed that serum soluble leptin receptor, known to antagonize leptin transport, had a 400-fold increase, probably contributing to the hyperleptinemia and reduced tissue uptake. Thus, the ELKO mutation unexpectedly increased the stability of leptin but suppressed its tissue uptake. These changes probably contribute to the known partial resistance of the ELKO mice to diet-induced obesity.

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Endothelial leptin receptor mutation provides partial resistance to diet-induced obesity

Cited by 15 publications

References 30 publications

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

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

Role of Astrocytes in Leptin Signaling

Endothelial cell leptin receptor mutant mice have hyperleptinemia and reduced tissue uptake

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