Obesity induces functional astrocytic leptin receptors in hypothalamus

Abstract

The possible role of astrocytes in the regulation of feeding has been overlooked. It is well-established that the endothelial cells constituting the blood-brain barrier transport leptin from blood to brain and that hypothalamic neurons respond to leptin to induce anorexic signaling. However, few studies have addressed the role of astrocytes in either leptin transport or cellular activation. We recently showed that the obese agouti viable yellow mouse has prominent astrocytic expression of the leptin receptor. In this study, we test the hypothesis that diet-induced obesity increases astrocytic leptin receptor expression and function in the hypothalamus. Double-labelling immunohistochemistry and confocal microscopic analysis showed that all astrocytes in the hypothalamus express leptin receptors. In adult obese mice, 2 months after being placed on a high-fat diet, there was a striking increase of leptin receptor (+) astrocytes, most prominent in the dorsomedial hypothalamus and arcuate nucleus. Agouti viable yellow mice with their adult-onset obesity showed similar changes, but the increase of leptin receptor (+) astrocytes was barely seen in ob/ob or db/db mice with their early-onset obesity and defective leptin systems. The marked leptin receptor protein expression in the astrocytes, shown with several antibodies against different receptor epitopes, was supported by RT-PCR detection of leptin receptor-a and -b mRNAs in primary hypothalamic astrocytes. Unexpectedly, the protein expression of GFAP, a marker of astrocytes, was also increased in adult-onset obesity. Real-time confocal imaging showed that leptin caused a robust increase of calcium signalling in primary astrocytes from the hypothalamus, confirming their functionality. The results indicate that metabolic changes in obese mice can rapidly alter leptin receptor expression and astrocytic activity, and that leptin receptor is responsible for leptin-induced calcium signalling in astrocytes. This novel and clinically relevant finding opens new avenues in astrocyte biology.

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

“…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.…”

“…In DIO, reactive astrocytes in the hypothalamus show upregulation of ObR (8). The ALKO mutation creates a mutant membrane-bound leptin receptor lacking intracellular signaling functions in astrocytes, but neuronal ObR expression is unaffected.…”

“…The percent fat/body wt (BW) was determined by NMR (Bruker Optics, Billerica, MA). BW was used as the denominator, as previously described (8,24).…”

“…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.…”

The Cannabinoid 1–Receptor Silent Antagonist O-2050 Attenuates Preference for High-Fat Diet and Activated Astrocytes in Mice

“…Moreover, obesity has been known to be associated with the induction of functional astrocytic leptin receptors in the hypothalamus, which is associated with feeding behavior (9). Therefore, we investigated whether 2-week HFD intake could increase the expression of GFAP in the hypothalamus.…”