Astrocyte Leptin Receptor (ObR) and Leptin Transport in Adult-Onset Obese Mice

Abstract

The agouti viable yellow (A vy) spontaneous mutation generates an unusual mouse phenotype of agouti-colored coat and adult-onset obesity with metabolic syndrome. Persistent production of agouti signaling protein in A vy mice antagonizes melanocortin receptors in the hypothalamus. To determine how this disruption of neuroendocrine circuits affects leptin transport across the blood-brain barrier (BBB), we measured leptin influx in A vy and B6 control mice after the development of obesity, hyperleptinemia, and increased adiposity. After iv bolus injection, (125)I-leptin crossed the BBB significantly faster in young (2 month old) B6 mice than in young A vy mice or in older (8 month old) mice of either strain. This difference was not observed by in situ brain perfusion studies, indicating the cause being circulating factors, such as elevated leptin levels or soluble receptors. Thus, A vy mice showed peripheral leptin resistance. ObRa, the main transporting receptor for leptin at the BBB, showed no change in mRNA expression in the cerebral microvessels between the age-matched (2 month old) A vy and B6 mice. Higher ObRb mRNA was seen in the A vy microvasculature with unknown significance. Immunofluorescent staining unexpectedly revealed that many of the ObR(+) cells were astrocytes and that the A vy mice showed significantly more ObR(+) astrocytes in the hypothalamus than the B6 mice. Although leptin permeation from the circulation was slower in the A vy mice, the increased ObR expression in astrocytes and increased ObRb mRNA in microvessels suggest the possibility of heightened central nervous system sensitivity to circulating leptin.

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

“…Although the ALKO mutation increased hypothalamic GFAP, DIO did not increase it in either strain; rather, it was reduced. The effect was apparently not mediated by ObRb, which is unchanged, and is consistent with the observation that neurons are the main source of ObRb in the hypothalamus (20,22). Leptin resistance, reflected by saturation of leptin transport across the BBB and desensitization of intracellular signaling with recruitment of antagonizing signaling elements, could also be lessened in the absence of astrocytic leptin signaling.…”

“…Thus we next determined pertinent changes in the hypothalamus of these mice. We tested whether the ALKO mutation modulates reactive astrogliosis in the hypothalamus, a hallmark of obesity-induced neuroinflammation (8,20,21). Consistent with published evidence, expression of hypothalamic GFAP was significantly increased in WT mice exposed to an HFD, but there was no significant change in GFAP expression in ALKO mice fed an HFD (Fig.…”

“…We have shown that adult-onset obesity specifically increases astrocytic ObR expression, whereas neuronal ObR does not show upregulation. The most pronounced increase in ObR expression with adult-onset obesity is not in neurons but in astrocytes, particularly in the hypothalamus (8,19,20). This raises a question of the functional significance of astrocytic leptin signaling in the development of obesity.…”

Glial cells and energy balance

“…However, hypothalamic glial cells not only participate in pathological events, such as the inflammatory response that occurs as a consequence of HFD consumption (Milanski et al 2009, Thaler et al 2012, Buckman et al 2014, Valdearcos et al 2014, Yan et al 2014), but they are also intricately involve in the physiological control of the surrounding neurons, including those dictating energy balance. The importance of this relationship is even further emphasized by the fact that these glial cells express receptors and systems of transport for numerous metabolic hormones and factors (Boyles et al 1985, Vielkind et al 1990, Zhu et al 1990, Vannucci et al 1997, Marty et al 2005, Pan et al 2008, Hsuchou et al 2009, Baquedano et al 2013, suggesting that at least part of the central effects of these metabolic signals are mediated through these non-neuronal cells. Thus, a deeper understanding of glial cell function will allow both a better understanding of their role in normal brain physiology, as well as their participation in pathological processes, and hopefully lead to the identification of new therapeutic targets for obesity treatment.…”

Leptin regulates glutamate and glucose transporters in hypothalamic astrocytes

“…Astrocytes were reported to participate in diverse neuroendocrine processes over 2 decades ago (4,5), although their importance in the control of appetite and energy balance has only recently come to the forefront (6)(7)(8)(9)(10)(11). Astrocytes and tanycytes, the specialized glial cells lining the third ventricle, transport nutrients into and within the brain, express receptors for numerous neuropeptides, neurotransmitters, and growth factors, produce neuroactive substances, and express key enzymes necessary for sensing and processing nutritional signals (2,6,(12)(13)(14)(15), situating them as prime targets for metabolic signals and control.…”