Obesity: Reversing leptin resistance

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Decreasing endoplasmic reticulum (ER) stress may sensitize the body to the key metabolic regulator leptin, revealing a potential therapeutic strategy for obesity.

Obesity prevalence continues to increase at an alarming rate, but current therapies are limited by side effects and modest efficacy. Now, writing in Cell Metabolism, Ozcan and colleagues show that decreasing endoplasmic reticulum (ER) stress may sensitize the body to the key metabolic regulator leptin, revealing a potential therapeutic strategy for obesity.


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The initial discovery of leptin, an adipocyte-derived hormone that acts on hypothalamic neurons to suppress appetite and regulate energy expenditure, raised hope for an obesity therapy. However, its therapeutic use is hampered by the development of leptin resistance in obese humans, a phenomenon for which the precise molecular mechanisms are not fully understood.

Previous studies have implicated ER stress — during which unfolded or misfolded proteins accumulate in the ER — in the development of obesity-induced insulin resistance and type 2 diabetes. This led Ozcan and colleagues to hypothesize that ER stress may also contribute to the development of leptin resistance and obesity.

First, the authors confirmed the existence of ER stress within the hypothalamus of obese mice. Indeed, activity of PERK (PRKR-like ER kinase) and IRE1 (inositol-requiring kinase 1) — key players in the unfolded protein response — was increased in mice on a high-fat diet, and these changes correlated with the development of obesity.

To further explore their theory, they next set out to establish a link between ER stress and leptin resistance. Pretreatment of leptin-receptor-expressing cells with the ER stress activators tunicamycin or dithiothreitol blocked the effects of subsequent leptin exposure. Likewise, in lean mice, hypothalamic tunicamycin infusion increased mRNA levels of leptin resistance markers, blocked the ability of injected leptin to activate downstream signalling pathways and increased food intake. Conversely, reversal of ER stress in vitro, by adenoviral cellular overexpression of XBP1 or ATF6 — transcription factors that act as master regulators of ER adaptive capacity — reversed tunicamycin-induced leptin inhibition.

To define a connection between these findings and obesity, the authors generated neuron-specific Xbp1-knockout mice, which exhibited high levels of ER stress and insensitivity to acute leptin injections. In contrast to control mice, knockout mice showed rapidly increasing leptin levels that reached up to 50-fold greater than control levels during a high-fat diet. Yet these mice still consumed more food, were less active and gained more weight than controls.

Finally, they investigated the ability of FDA-approved chemical chaperones — known to enhance the activity of ER folding machinery — to reverse leptin resistance. Oral 4-phenylbutyrate or tauroursodeoxycholic acid treatment decreased hypothalamic ER stress in diet-induced obese mice and sensitized them to leptin injection: food intake, body fat and body weight were all reduced, whereas O₂ consumption and heat production were increased. Similarly, hypothalamic ER stress was reduced in the ob–ob obese mouse model, which became sensitive to low doses of leptin.

In summary, these findings demonstrate a central role of ER stress in leptin resistance and identify the first known class of leptin sensitizers, re-establishing the possible use of leptin as an obesity therapy.

Sarah Crunkhorn

References

Ozcan, L. et al. Endoplasmic reticulum stress plays a central role in development of leptin resistance. Cell Metab. 9, 35–51 (2009) | Article | PubMed |
Cooke, D. & Bloom, S. The obesity pipeline: current strategies in the development of anti-obesity drugs. Nature Rev. Drug Discov. 5, 919–931 (2006) | Article | PubMed |