Modulation of AgRP-neuronal function by SOCS3 as an initiating event in diet-induced hypothalamic leptin resistance

Chronic consumption of a fat-rich diet leads to attenuation of leptin signaling in hypothalamic neurons, a hallmark feature of cellular leptin resistance. To date, little is known about the temporal and spatial dysregulation of neuronal function under conditions of nutrient excess. We show that agou...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2013-02, Vol.110 (8), p.E697-E706
Main Authors: Olofsson, Louise E, Unger, Elizabeth K, Cheung, Clement C, Xu, Allison W
Format: Article
Language:English
Subjects:
Animals
Biological Sciences
Brain
Cells
Cytokines
Diet
Dietary Fats - administration & dosage
Hypothalamus - cytology
Hypothalamus - physiopathology
Leptin - physiology
Mice
Neurons
Neurons - metabolism
Neurons - physiology
Plasma
PNAS Plus
Suppressor of Cytokine Signaling 3 Protein
Suppressor of Cytokine Signaling Proteins - physiology
Up-Regulation
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Summary:Chronic consumption of a fat-rich diet leads to attenuation of leptin signaling in hypothalamic neurons, a hallmark feature of cellular leptin resistance. To date, little is known about the temporal and spatial dysregulation of neuronal function under conditions of nutrient excess. We show that agouti-related protein (AgRP)-expressing neurons precede proopiomelanocortin neurons in developing diet-induced cellular leptin resistance. High-fat diet-induced up-regulation of suppressor of cytokine signaling-3 (SOCS3) occurs in AgRP neurons before proopiomelanocortin and other hypothalamic neurons. SOCS3 expression in AgRP neurons increases after 2 d of high-fat feeding, but reduces after switching to a low-fat diet for 1 d. Consistently, transgenic overexpression of SOCS3 in AgRP neurons produces metabolic phenotypes resembling those observed after short-term high-fat feeding. We further show that AgRP neurons are the predominant cell type situated outside the blood-brain barrier in the mediobasal hypothalamus. AgRP neurons are more responsive to low levels of circulating leptin, but they are also more prone to development of leptin resistance in response to a small increase in blood leptin concentrations. Collectively, these results suggest that AgRP neurons are able to sense slight changes in plasma metabolic signals, allowing them to serve as first-line responders to fluctuation of energy intake. Furthermore, modulation of SOCS3 expression in AgRP neurons may play a dynamic and physiological role in metabolic fine tuning in response to short-term changes of nutritional status.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1218284110