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Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity

Karim El-Haschimi, Dominique D. Pierroz, Stanley M. Hileman, Christian Bjørbæk, Jeffrey S. Flier

Published in Volume 105, Issue 12

J Clin Invest. 2000; 105(12):1827 doi:10.1172/JCI9842

Abstract | Full text | PDF

O besity in humans and in rodents is usually associated with high circulating leptin levels and leptin resistance. To examine the molecular basis for leptin resistance, we determined the ability of leptin to induce hypothalamic STAT3 (signal transducer and activator of transcription) signaling in C57BL/6J mice fed either low-fat or high-fat diets. In mice fed the low-fat diet, leptin activated STAT3 signaling when administered via the intraperitoneal (ip) or the intracerebroventricular (icv) route, with the half-maximal dose being 30-fold less when given by the icv route. The high-fat diet increased body-weight gain and plasma leptin levels. After 4 weeks on the diet, hypothalamic STAT3 signaling after ip leptin administration was equivalent in both diet groups. In contrast, peripherally administered leptin was completely unable to activate hypothalamic STAT3 signaling, as measured by gel shift assay after 15 weeks of high-fat diet. Despite the absence of detectable signaling after peripheral leptin at 15 weeks, the mice fed the high-fat diet retained the capacity to respond to icv leptin, although the magnitude of STAT3 activation was substantially reduced. These results suggest that leptin resistance induced by a high-fat diet evolves during the course of the diet and has at least two independent causes: an apparent defect in access to sites of action in the hypothalamus that markedly limits the ability of peripheral leptin to activate hypothalamic STAT signaling, and an intracellular signaling defect in leptin-responsive hypothalamic neurons that lies upstream of STAT3 activation.

Leptin Access into the Brain: A Saturated Transport System vs. a Post-receptor Defect in Obesity

Barto Burguera MD, Ph.D and Marta E. Couce MD, Ph.D | burguerab@msx.dept-med.pitt.edu

Divisions of Endocrinology and Neuropathology. University of Pittsburgh Medical Center

The manuscript by El-Haschimi and colleagues, evaluating leptin resistance by determination of leptin’s ability to induce hypothalamic STAT3 signaling in mice fed either a low-fat or high fat diet (HFD), raises important issues regarding the mechanism of leptin access to the hypothalamus in obesity. The authors postulate that the leptin resistance induced by an HFD has at least two independent causes: First, an apparent defect in leptin access to it sites of action in the hypothalamus, and second an intracellular signaling defect in leptin responsive hypothalamic neurons. Several studies support their first observation (1-4). Leptin transport system seems to be saturated at near-physiological concentrations in lean individuals. Therefore, the elevated leptin levels observed in obesity can produce no biological effects because the system is already saturated. This circumstance does not seem to reflect an intrinsic transport defect, but a consequence of the physiological saturation of the leptin receptor at the brain blood barrier (BBB) level, secondary to hyperleptinemia. Interestingly, since intracerebroventricular (icv) leptin administration had a 75% lower capacity to activate STAT3 after 15 weeks of HFD compared to lean mice, the authors postulate that an intracellular signaling defect might also contribute to leptin resistance present in HFD group (higher doses of intraperitoneal leptin had no effect stimulating STAT3 after 15 weeks of HFD). This is certainly a possibility, but an important issue needs to be taken into consideration. Since the ependymal lining separates the ventricular space and the hypothalamus, cerebro-spinal fluid (CSF) concentrations of leptin may not correlate with actual hypothalamic leptin levels. Leptin administered by an icv route must cross the ependymal barrier before reaching the hypothalamus. It would be very likely that, due to the hyperleptinemia characteristic of obese individuals, the leptin receptors present in the ependimal cells are already saturated. The authors did not measured leptin levels in the CSF but, after 100 days of HFD, the plasma leptin levels were very high at 28 ng/ml. This circumstance would contribute to limit the access of leptin to the hypothalamus and might be responsible for the reduced capacity of icv leptin to activate hypothalamic STAT3 after 15 weeks of HFD. The possibility that obese individuals have a post-receptor leptin defect in the brain rather than a saturated leptin receptor mechanism at the BBB endothelium and ependymal lining, remains an unsolved issue open to speculation.
1. Banks W.A. 1996. Leptin enters the brain by a saturable system independent of insulin. Peptides 17:305-31.
2. Karonen S.L., et al. 1998. Is brain uptake of leptin in vivo saturable and reduced by fasting? Eur J Nucl Med 25:607-612.
3. Banks W.A. et al. 2000. Partial saturation and regional variation in the blood to-brain transport of leptin in normal weight mice. Am J Physiol Endocrinol Metab 278:E1158-65.
4. Burguera B. et al. 2000. Obesity is associated with a decreased of leptin transport across the blood brain barrier in rats. Diabetes. 49:1219-1223.