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fDWI Evaluation of Hypothalamic Appetite Regulation Pathways in Mice Genetically Deficient in Leptin or Neuropeptide Y

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Abstract

We evaluate the contribution of leptin-dependent anorexigenic pathways and neuropeptide Y (NPY)-dependent orexigenic pathways to the changes in hypothalamic water diffusion parameters observed in vivo by functional diffusion weighted MRI (fDWI). Mice genetically deficient in leptin (B6.V-Lep ob/J) or NPY (129S-Npy tm1Rpa/J) and the corresponding wild-type controls, were subjected to sequential isocaloric feeding, fasting and recovery regimes. Non-invasive fDWI measurements were performed under these conditions, and complemented with parallel determinations of food and water consumption, respiratory exchange ratio (RER), locomotor activity and endocrine profiles. Control mice showed significant increases in hypothalamic water diffusion parameters upon fasting, returning to normal values in the recovery period. Leptin deficient mice depicted permanently increased water diffusion parameters under all feeding conditions as compared to wild type controls, without important changes upon fasting or recovery. These results paralleled sustained increases in food and water intake, significantly augmented body weight, and decreased RER values or locomotor activity, thus configuring an obese phenotype. NPY-deficient mice showed significantly reduced increases (or even slight decreases) in the water diffusion parameters upon fasting as compared to wild type controls, paralleled by decreased food and water intake during the recovery period. In conclusion, leptin deficiency results in sustained orexigenic stimulation, leading to increased water diffusion parameters, while NPY deficiency lead to reduced orexigenic stimulation and water diffusion parameters. Diffusion changes are proposed to reflect net astrocytic volume changes induced by the balance between the orexigenic and anorexigenic firings of AgRP/NPY and POMC/CART neurons, respectively. Together, our results suggest that fDWI provides an adequate tool to investigate hypothalamic appetite disorders.

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Abbreviations

A–P:

Antero–posterior direction

BOLD:

Blood oxygenation level dependent contrast

Dslow :

Slow diffusion coefficient

Dfast :

Fast diffusion coefficient

FDP:

Fast diffusion phase

fDWI:

Functional diffusion weighted magnetic resonance imaging

H–F:

Head–foot direction

L–R:

Left–right direction

MRI:

Magnetic resonance imaging

NPY:

Neuropeptide Y

PET:

Positron emission tomography

RER:

Respiratory exchange ratio

SDP:

Slow diffusion phase

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Acknowledgments

Authors wish to express their gratitude to Drs. Carlota Largo and Victor Caz from the Hospital Universitario La Paz for the hormonal tests, to Mr. Javier Pérez CSIC for professional drafting of the illustrations, to Mrs. Teresa Navarro CSIC for expert maintenance of the MRI instrumentation and to Mrs. Patricia Sánchez CSIC for proficient technical assistance with animal housing and handling. The Phenomaster and MRI instrumentations are Central CSIC Research Resources of the Institute of Biomedical Research “Alberto Sols”. This work was supported in part by Grants SAF-2008-01327, SAF2011-23622 and IPT-2012-1331-006000 to SC, Grant CTQ-2010-20960-C02-02 to PLL, Grants S-BIO-2006-0170 and S2010/BMD-2349 to S.C. and PLL. BL held a predoctoral fellowship from the Spanish Ministry of Science and Technology (BES 2009-027615).

Conflict of interest

Authors disclose no conflict of interest.

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Author notes

  1. Blanca Lizarbe

    Present address: Laboratory for Functional and Metabolic Imaging (LIFMET), Êcole Polytechnique Fédéral Lausanne, EPFL SB IPSB LIFMET, CH F1 632 (Bâtiment CH), Station 6, 1015, Lausanne, Switzerland

Authors and Affiliations

  1. Instituto Investigaciones Biomédicas “Alberto Sols” CSIC-UAM, c/Arturo Duperier 4, 28029, Madrid, Spain

    Blanca Lizarbe, Pilar López-Larrubia & Sebastián Cerdán

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  1. Blanca Lizarbe
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  2. Pilar López-Larrubia
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  3. Sebastián Cerdán
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Correspondence to Sebastián Cerdán.

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Special Issue: In Honor of Dr. Gerald Dienel.

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Lizarbe, B., López-Larrubia, P. & Cerdán, S. fDWI Evaluation of Hypothalamic Appetite Regulation Pathways in Mice Genetically Deficient in Leptin or Neuropeptide Y. Neurochem Res 40, 2628–2638 (2015). https://doi.org/10.1007/s11064-015-1596-z

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