Elsevier

Molecular Metabolism

Volume 6, Issue 8, August 2017, Pages 897-908
Molecular Metabolism

Original Article
Dietary sugars, not lipids, drive hypothalamic inflammation

https://doi.org/10.1016/j.molmet.2017.06.008Get rights and content
Under a Creative Commons license
open access

Highlights

  • HCHF, but not LCHF diets, induce obesity and increase the hypothalamic inflammatory response.

  • A HCHF diet increases N-epsilon-(carboxymethyl)lysine content in hypothalamic neurons in the ARC.

  • Obesity and metabolic symptoms induced by a HCHF diet are improved in mice lacking functional RAGE and ALCAM genes.

  • Lacking RAGE and ALCAM prevents the hypothalamic inflammatory response and angiogenesis that occur on a HCHF diet.

Abstract

Objective

The hypothalamus of hypercaloric diet-induced obese animals is featured by a significant increase of microglial reactivity and its associated cytokine production. However, the role of dietary components, in particular fat and carbohydrate, with respect to the hypothalamic inflammatory response and the consequent impact on hypothalamic control of energy homeostasis is yet not clear.

Methods

We dissected the different effects of high-carbohydrate high-fat (HCHF) diets and low-carbohydrate high-fat (LCHF) diets on hypothalamic inflammatory responses in neurons and non-neuronal cells and tested the hypothesis that HCHF diets induce hypothalamic inflammation via advanced glycation end-products (AGEs) using mice lacking advanced glycation end-products (AGEs) receptor (RAGE) and/or the activated leukocyte cell-adhesion molecule (ALCAM).

Results

We found that consumption of HCHF diets, but not of LCHF diets, increases microgliosis as well as the presence of N(ε)-(Carboxymethyl)-Lysine (CML), a major AGE, in POMC and NPY neurons of the arcuate nucleus. Neuron-secreted CML binds to both RAGE and ALCAM, which are expressed on endothelial cells, microglia, and pericytes. On a HCHF diet, mice lacking the RAGE and ALCAM genes displayed less microglial reactivity and less neovasculature formation in the hypothalamic ARC, and this was associated with significant improvements of metabolic disorders induced by the HCHF diet.

Conclusions

Combined overconsumption of fat and sugar, but not the overconsumption of fat per se, leads to excessive CML production in hypothalamic neurons, which, in turn, stimulates hypothalamic inflammatory responses such as microgliosis and eventually leads to neuronal dysfunction in the control of energy metabolism.

Keywords

Microglia
POMC
Obesity
Pericytes
Angiogenesis

Cited by (0)

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Yuanqing Gao and Maximilian Bielohuby contributed equally to this work.