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Animal Models

Is leptin resistance the cause or the consequence of diet-induced obesity?

International Journal of Obesity volume 42, pages 1445–1457 (2018)Cite this article

Subjects

Abstract

Background/objectives

Obesity is strongly associated with leptin resistance. It is unclear whether leptin resistance results from the (over)consumption of energy-dense diets or if reduced leptin sensitivity is also a pre-existing factor in rodent models of diet-induced obesity (DIO). We here tested whether leptin sensitivity on a chow diet predicts subsequent weight gain and leptin sensitivity on a free choice high-fat high-sucrose (fcHFHS) diet.

Methods

Based upon individual leptin sensitivity on chow diet, rats were grouped in leptin sensitive (LS, n = 22) and leptin resistant (LR, n = 19) rats (P = 0.000), and the development of DIO on a fcHFHS diet was compared. The time-course of leptin sensitivity was measured over weeks in individual rats.

Results

Both on a chow and a fcHFHS diet, high variability in leptin sensitivity was observed between rats, but not over time per individual rat. Exposure to the fcHFHS diet revealed that LR rats were more prone to develop DIO (P = 0.013), which was independent of caloric intake (p ≥ 0.320) and the development of diet-induced leptin resistance (P = 0.769). Reduced leptin sensitivity in LR compared with LS rats before fcHFHS diet exposure, was associated with reduced leptin-induced phosphorylated signal transducer and activator of transcription 3 (pSTAT3) levels in the dorsomedial and ventromedial hypothalamus (P ≤ 0.049), but not the arcuate nucleus (P = 0.558).

Conclusions

A pre-existing reduction in leptin sensitivity determines the susceptibility to develop excessive DIO after fcHFHS diet exposure. Rats with a pre-existing reduction in leptin sensitivity develop excessive DIO without eating more calories or altering their leptin sensitivity.

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Acknowledgements

We thank Diana van Tuijl, Inge Wolterink-Donselaar, Jos Brits, Harrie van der Eerden, and Henk Spierenburg for their practical assistance.

Funding

This research was supported by the Dutch Technology Foundation STW (grant 12264), which is part of the Netherlands Organisation for Scientific Research (NWO), and which is partly funded by the Ministry of Economic Affairs, and by the NWO under project number 863.13.018 (NWO/ALW Veni grant).

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Authors and Affiliations

  1. Brain Center Rudolf Magnus, Department of Translational Neuroscience, University Medical Center Utrecht, Utrecht University, Utrecht, 3584 CG, The Netherlands

    Kathy C. G. de Git, Céline Peterse, Sanne Beerens, Mieneke C. M. Luijendijk, Geoffrey van der Plasse & Roger A. H. Adan

  2. Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, 1105 AZ, The Netherlands

    Susanne E. la Fleur

  3. Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

    Roger A. H. Adan

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Correspondence to Roger A. H. Adan.

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de Git, K.C.G., Peterse, C., Beerens, S. et al. Is leptin resistance the cause or the consequence of diet-induced obesity?. Int J Obes 42, 1445–1457 (2018). https://doi.org/10.1038/s41366-018-0111-4

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