Article | Published:

Animal Models

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

International Journal of Obesity (2018) | Download Citation




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.


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.


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).


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.

  • Subscribe to International Journal of Obesity for full access:



Additional access options:

Already a subscriber?  Log in  now or  Register  for online access.


  1. 1.

    Nguyen DM, El-Serag HB. The epidemiology of obesity. Gastroenterol Clin North Am. 2010;39:1–7.

  2. 2.

    Pandit R, Mercer JG, Overduin J, la Fleur SE, Adan RA. Dietary factors affect food reward and motivation to eat. Obes Facts. 2012;5:221–42.

  3. 3.

    Schwartz MW, Peskind E, Raskind M, Boyko EJ, Porte D Jr Cerebrospinal fluid leptin levels: relationship to plasma levels and to adiposity in humans. Nat Med. 1996;2:589–93.

  4. 4.

    Considine RV, Stephens TW, Nyce M, Ohannesian JP, Marco CC, McKee LJ, et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. New Engl J Med. 1996;334:292.

  5. 5.

    Heymsfield SB, Greenberg AS, Fujioka K, Dixon RM, Kushner R, Hunt T, et al. Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA. 1999;282:1568–75.

  6. 6.

    Caro JF, Kolaczynski JW, Nyce MR, Ohannesian JP, Opentanova I, Goldman WH, et al. Decreased cerebrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance. Lancet. 1996;348:159–61.

  7. 7.

    Apolzan JW, Harris RB. Rapid onset and reversal of peripheral and central leptin resistance in rats offered chow, sucrose solution, and lard. Appetite. 2013;60:65–73.

  8. 8.

    Myers MG Jr Leptin keeps working, even in obesity. Cell Metab. 2015;21:791–2.

  9. 9.

    Ottaway N, Mahbod P, Rivero B, Norman LA, Gertler A, D’Alessio DA, et al. Diet-induced obese mice retain endogenous leptin action. Cell Metab. 2015;21:877–82.

  10. 10.

    Lin L, Martin R, Schaffhauser AO, York DA. Acute changes in the response to peripheral leptin with alteration in the diet composition. Am J Physiol Regul Integr Comp Physiol. 2001;280:R504–9.

  11. 11.

    Shapiro A, Tumer N, Gao Y, Cheng KY, Scarpace PJ. Prevention and reversal of diet-induced leptin resistance with a sugar-free diet despite high fat content. Br J Nutr. 2011;106:390–7.

  12. 12.

    Haring SJ, Harris RB. The relation between dietary fructose, dietary fat and leptin responsiveness in rats. Physiol Behav. 2011;104:914–22.

  13. 13.

    Scarpace PJ, Matheny M, Tumer N, Cheng KY, Zhang Y. Leptin resistance exacerbates diet-induced obesity and is associated with diminished maximal leptin signalling capacity in rats. Diabetologia. 2005;48:1075–83.

  14. 14.

    Frederich RC, Hamann A, Anderson S, Lollmann B, Lowell BB, Flier JS. Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin action. Nat Med. 1995;1:1311–4.

  15. 15.

    Harris RB, Apolzan JW. Changes in glucose tolerance and leptin responsiveness of rats offered a choice of lard, sucrose, and chow. Am J Physiol Regul Integr Comp Physiol. 2012;302:R1327–39.

  16. 16.

    van den Heuvel JK, Eggels L, van Rozen AJ, Luijendijk MC, Fliers E, Kalsbeek A, et al. Neuropeptide Y and leptin sensitivity is dependent on diet composition. J Neuroendocrinol. 2014;26:377–85.

  17. 17.

    Enriori PJ, Evans AE, Sinnayah P, Jobst EE, Tonelli-Lemos L, Billes SK, et al. Diet-induced obesity causes severe but reversible leptin resistance in arcuate melanocortin neurons. Cell Metab. 2007;5:181–94.

  18. 18.

    Enriori PJ, Sinnayah P, Simonds SE, Garcia Rudaz C, Cowley MA. Leptin action in the dorsomedial hypothalamus increases sympathetic tone to brown adipose tissue in spite of systemic leptin resistance. J Neurosci. 2011;31:12189–97.

  19. 19.

    Mercer JG, Hoggard N, Williams LM, Lawrence CB, Hannah LT, Trayhurn P. Localization of leptin receptor mRNA and the long form splice variant (Ob-Rb) in mouse hypothalamus and adjacent brain regions by in situ hybridization. FEBS Lett. 1996;387:113–6.

  20. 20.

    Elmquist JK, Bjorbaek C, Ahima RS, Flier JS, Saper CB. Distributions of leptin receptor mRNA isoforms in the rat brain. J Comp Neurol. 1998;395:535–47.

  21. 21.

    Hakansson ML, Brown H, Ghilardi N, Skoda RC, Meister B. Leptin receptor immunoreactivity in chemically defined target neurons of the hypothalamus. J Neurosci. 1998;18:559–72.

  22. 22.

    Munzberg H, Flier JS, Bjorbaek C. Region-specific leptin resistance within the hypothalamus of diet-induced obese mice. Endocrinology. 2004;145:4880–9.

  23. 23.

    Desai BN, Harris RB. An acute method to test leptin responsiveness in rats. Am J Physiol Regul Integr Comp Physiol. 2014;306:R852–60.

  24. 24.

    Scarpace PJ, Zhang Y. Leptin resistance: a prediposing factor for diet-induced obesity. Am J Physiol Regul Integr Comp Physiol. 2009;296:R493–500.

  25. 25.

    Bates SH, Stearns WH, Dundon TA, Schubert M, Tso AW, Wang Y, et al. STAT3 signalling is required for leptin regulation of energy balance but not reproduction. Nature. 2003;421:856.

  26. 26.

    Gao Q, Wolfgang MJ, Neschen S, Morino K, Horvath TL, Shulman GI, et al. Disruption of neural signal transducer and activator of transcription 3 causes obesity, diabetes, infertility, and thermal dysregulation. Proc Natl Acad Sci USA. 2004;101:4661–6.

  27. 27.

    Shapiro A, Mu W, Roncal C, Cheng KY, Johnson RJ, Scarpace PJ. Fructose-induced leptin resistance exacerbates weight gain in response to subsequent high-fat feeding. Am J Physiol Regul Integr Comp Physiol. 2008;295:R1370–5.

  28. 28.

    Ruffin MP, Adage T, Kuipers F, Strubbe JH, Scheurink AJ, van Dijk G. Feeding and temperature responses to intravenous leptin infusion are differential predictors of obesity in rats. Am J Physiol Regul Integr Comp Physiol. 2004;286:R756–63.

  29. 29.

    Levin BE, Dunn-Meynell AA. Reduced central leptin sensitivity in rats with diet-induced obesity. Am J Physiol Regul Integr Comp Physiol. 2002;283:R941–8.

  30. 30.

    Steffens AB. A method of frequent sampling blood and continuous infusion of fluids in the rat without disturbing the animal. Physiol Behav. 1969;4:836.

  31. 31.

    Munzberg H, Huo L, Nillni EA, Hollenberg AN, Bjorbaek C. Role of signal transducer and activator of transcription 3 in regulation of hypothalamic proopiomelanocortin gene expression by leptin. Endocrinology. 2003;144:2121–31.

  32. 32.

    la Fleur SE, van Rozen AJ, Luijendijk MC, Groeneweg F, Adan RA. A free-choice high-fat high-sugar diet induces changes in arcuate neuropeptide expression that support hyperphagia. Int J Obes (Lond). 2010;34:537–46.

  33. 33.

    Levin BE, Dunn-Meynell AA, Banks WA. Obesity-prone rats have normal blood–brain barrier transport but defective central leptin signaling before obesity onset. Am J Physiol Regul Integr Comp Physiol. 2004;286:R143–50.

  34. 34.

    Wilson JL, Enriori PJ. A talk between fat tissue, gut, pancreas and brain to control body weight. Mol Cell Endocrinol. 2015;418:108–19.

  35. 35.

    Zhou Y, Rui L. Leptin signaling and leptin resistance. Front Med. 2013;7:207–22.

  36. 36.

    Satoh N, Ogawa Y, Katsuura G, Hayase M, Tsuji T, Imagawa K, et al. The arcuate nucleus as a primary site of satiety effect of leptin in rats. Neurosci Lett. 1997;224:149–52.

  37. 37.

    Morton GJ, Niswender KD, Rhodes CJ, Myers MG Jr, Blevins JE, Baskin DG, et al. Arcuate nucleus-specific leptin receptor gene therapy attenuates the obesity phenotype of Koletsky (fa(k)/fa(k)) rats. Endocrinology. 2003;144:2016–24.

  38. 38.

    Levin BE, Dunn-Meynell AA, Ricci M, Cummings DE. Abnormalities of leptin and ghrelin regulation in obesity-prone juvenile rats. Am J Physiol Endocrinol Metab. 2003;285:E949–E957.

  39. 39.

    Irani BG, Dunn-Meynell AA, Levin BE. Altered hypothalamic leptin, insulin and melanocortin binding associated with moderate fat diet and predisposition to obesity. Endocrinology. 2007;148:310–6.

  40. 40.

    Bouret SG, Gorski JN, Patterson CM, Chen S, Levin BE, Simerly RB. Hypothalamic neural projections are permanently disrupted in diet-induced obese rats. Cell Metab. 2008;7:179–85.

  41. 41.

    Dodd GT, Worth AA, Nunn N, Korpal AK, Bechtold DA, Allison MB, et al. The thermogenic effect of leptin is dependent on a distinct population of prolactin-releasing peptide neurons in the dorsomedial hypothalamus. Cell Metab. 2014;20:639–49.

  42. 42.

    Rezai-Zadeh K, Yu S, Jiang Y, Laque A, Schwartzenburg C, Morrison CD, et al. Leptin receptor neurons in the dorsomedial hypothalamus are key regulators of energy expenditure and body weight, but not food intake. Mol Metab. 2014;3:681–93.

  43. 43.

    Minokoshi Y, Haque MS, Shimazu T. Microinjection of leptin into the ventromedial hypothalamus increases glucose uptake in peripheral tissues in rats. Diabetes. 1999;48:287–91.

  44. 44.

    Pandit R, Beerens S, Adan RAH. Role of leptin in energy expenditure: the hypothalamic perspective. Am J Physiol Regul Integr Comp Physiol. 2017;312:R938–47.

  45. 45.

    Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006;444:1027–31.

  46. 46.

    Schele E, Grahnemo L, Anesten F, Hallen A, Backhed F, Jansson JO. The gut microbiota reduces leptin sensitivity and the expression of the obesity-suppressing neuropeptides proglucagon (Gcg) and brain-derived neurotrophic factor (Bdnf) in the central nervous system. Endocrinology. 2013;154:3643–51.

  47. 47.

    Park DY, Ahn YT, Park SH, Huh CS, Yoo SR, Yu R, et al. Supplementation of Lactobacillus curvatus HY7601 and Lactobacillus plantarum KY1032 in diet-induced obese mice is associated with gut microbial changes and reduction in obesity. PLOS One. 2013;8:e59470.

Download references


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


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).

Author information


  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


  1. Search for Kathy C. G. de Git in:

  2. Search for Céline Peterse in:

  3. Search for Sanne Beerens in:

  4. Search for Mieneke C. M. Luijendijk in:

  5. Search for Geoffrey van der Plasse in:

  6. Search for Susanne E. la Fleur in:

  7. Search for Roger A. H. Adan in:

Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Roger A. H. Adan.

Electronic supplementary material

About this article

Publication history






Rights and permissions

To obtain permission to re-use content from this article visit RightsLink.