Obesity is associated with hypothalamic injury in rodents and humans
Joshua P. Thaler, … , Matthias H. Tschöp, Michael W. Schwartz
Joshua P. Thaler, … , Matthias H. Tschöp, Michael W. Schwartz
Published December 27, 2011
Citation Information: J Clin Invest. 2012;122(1):153-162. https://doi.org/10.1172/JCI59660.
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Research Article

Obesity is associated with hypothalamic injury in rodents and humans

Abstract

Rodent models of obesity induced by consuming high-fat diet (HFD) are characterized by inflammation both in peripheral tissues and in hypothalamic areas critical for energy homeostasis. Here we report that unlike inflammation in peripheral tissues, which develops as a consequence of obesity, hypothalamic inflammatory signaling was evident in both rats and mice within 1 to 3 days of HFD onset, prior to substantial weight gain. Furthermore, both reactive gliosis and markers suggestive of neuron injury were evident in the hypothalamic arcuate nucleus of rats and mice within the first week of HFD feeding. Although these responses temporarily subsided, suggesting that neuroprotective mechanisms may initially limit the damage, with continued HFD feeding, inflammation and gliosis returned permanently to the mediobasal hypothalamus. Consistent with these data in rodents, we found evidence of increased gliosis in the mediobasal hypothalamus of obese humans, as assessed by MRI. These findings collectively suggest that, in both humans and rodent models, obesity is associated with neuronal injury in a brain area crucial for body weight control.

Authors

Joshua P. Thaler, Chun-Xia Yi, Ellen A. Schur, Stephan J. Guyenet, Bang H. Hwang, Marcelo O. Dietrich, Xiaolin Zhao, David A. Sarruf, Vitaly Izgur, Kenneth R. Maravilla, Hong T. Nguyen, Jonathan D. Fischer, Miles E. Matsen, Brent E. Wisse, Gregory J. Morton, Tamas L. Horvath, Denis G. Baskin, Matthias H. Tschöp, Michael W. Schwartz

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Figure 1

Time course of hypothalamic inflammation after the onset of HFD feeding.

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Time course of hypothalamic inflammation after the onset of HFD feeding....
(A and B) Quantification of mRNA encoding proinflammatory cytokines (Il1b, Il6, Tnfa) and NF-κB pathway genes (Nfkbia, Ikbkb) in (A) hypothalamus and (B) liver of rats fed either standard chow (white bars) or HFD (gray bars) for 20 weeks (n = 6/group). *P < 0.05 versus chow-fed controls. (C–E) Effect of 4 weeks of HFD feeding (gray bars) on proinflammatory cytokine gene expression in rat (C) hypothalamus, (D) liver, and (E) white adipose tissue compared with that in chow-fed controls (white bars) (n = 6/group). *P < 0.05 versus chow-fed controls. (F) Total weight gain (black bars), fat mass gain (white bars), and (G) average (avg) daily food intake (kcal/d) of rats (n = 6/group) fed chow for 2 weeks or HFD for up to 28 days. *P < 0.05 versus chow-fed controls. (H) Comparison of daily food intake (kcal) in rats (n = 6/group) fed chow (gray) or HFD (black) for 14 days. *P < 0.05 versus chow-fed controls. (I) Time course of induction of mRNA encoding inflammatory mediators, including proinflammatory cytokine (Il1b, Il6, Tnfa), cytokine pathway (Socs3), and NF-κB pathway (Nfkbia, Ikbkb, Ikbke) gene expression in the hypothalamus of rats fed chow or HFD for up to 28 days (n = 6/group). All mRNA species were quantified relative to 18S and Gapdh housekeeping gene expression (by ΔΔCT method) and presented as fold change relative to chow-fed controls [fold chow]. The dashed line in I represents the level of expression equal to chow-fed controls. *P < 0.05 versus chow.