Hypothalamic Mitochondrial Dysfunction As a Target in Obesity and Metabolic Disease

Overview

Journal Front Endocrinol (Lausanne)

Specialty Endocrinology

Date 2018 Jun 16

PMID 29904371

Citations 15

Authors

Juan Cunarro

Sabela Casado

Javier Lugilde

Sulay Tovar

Affiliations

Soon will be listed here.

Abstract

Mitochondria are important organelles for the adaptation to energy demand that play a central role in bioenergetics metabolism. The mitochondrial architecture and mitochondrial machinery exhibits a high degree of adaptation in relation to nutrient availability. On the other hand, its disruption markedly affects energy homeostasis. The brain, more specifically the hypothalamus, is the main hub that controls energy homeostasis. Nevertheless, until now, almost all studies in relation to mitochondrial dysfunction and energy metabolism have focused in peripheral tissues like brown adipose tissue, muscle, and pancreas. In this review, we highlight the relevance of the hypothalamus and the influence on mitochondrial machinery in its function as well as its consequences in terms of alterations in both energy and metabolic homeostasis.

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References

Otera H, Wang C, Cleland M, Setoguchi K, Yokota S, Youle R . Mff is an essential factor for mitochondrial recruitment of Drp1 during mitochondrial fission in mammalian cells. J Cell Biol. 2010; 191(6):1141-58. PMC: 3002033. DOI: 10.1083/jcb.201007152. View

Jheng H, Huang S, Kuo H, Hughes M, Tsai Y . Molecular insight and pharmacological approaches targeting mitochondrial dynamics in skeletal muscle during obesity. Ann N Y Acad Sci. 2015; 1350:82-94. DOI: 10.1111/nyas.12863. View

Legesse-Miller A, Massol R, Kirchhausen T . Constriction and Dnm1p recruitment are distinct processes in mitochondrial fission. Mol Biol Cell. 2003; 14(5):1953-63. PMC: 165089. DOI: 10.1091/mbc.e02-10-0657. View

Zorzano A, Claret M . Implications of mitochondrial dynamics on neurodegeneration and on hypothalamic dysfunction. Front Aging Neurosci. 2015; 7:101. PMC: 4461829. DOI: 10.3389/fnagi.2015.00101. View

Ozcan L, Ergin A, Lu A, Chung J, Sarkar S, Nie D . Endoplasmic reticulum stress plays a central role in development of leptin resistance. Cell Metab. 2009; 9(1):35-51. DOI: 10.1016/j.cmet.2008.12.004. View

Ishihara N, Nomura M, Jofuku A, Kato H, Suzuki S, Masuda K . Mitochondrial fission factor Drp1 is essential for embryonic development and synapse formation in mice. Nat Cell Biol. 2009; 11(8):958-66. DOI: 10.1038/ncb1907. View

Portela L, Gnoatto J, Brochier A, Haas C, de Assis A, de Carvalho A . Intracerebroventricular metformin decreases body weight but has pro-oxidant effects and decreases survival. Neurochem Res. 2014; 40(3):514-23. DOI: 10.1007/s11064-014-1496-7. View

Rowland A, Voeltz G . Endoplasmic reticulum-mitochondria contacts: function of the junction. Nat Rev Mol Cell Biol. 2012; 13(10):607-25. PMC: 5111635. DOI: 10.1038/nrm3440. View

Fealy C, Mulya A, Lai N, Kirwan J . Exercise training decreases activation of the mitochondrial fission protein dynamin-related protein-1 in insulin-resistant human skeletal muscle. J Appl Physiol (1985). 2014; 117(3):239-45. PMC: 4122691. DOI: 10.1152/japplphysiol.01064.2013. View

10.

Raza H, John A, Howarth F . Increased oxidative stress and mitochondrial dysfunction in zucker diabetic rat liver and brain. Cell Physiol Biochem. 2015; 35(3):1241-51. DOI: 10.1159/000373947. View

11.

Parone P, Da Cruz S, Tondera D, Mattenberger Y, James D, Maechler P . Preventing mitochondrial fission impairs mitochondrial function and leads to loss of mitochondrial DNA. PLoS One. 2008; 3(9):e3257. PMC: 2532749. DOI: 10.1371/journal.pone.0003257. View

12.

Pipatpiboon N, Pratchayasakul W, Chattipakorn N, Chattipakorn S . PPARγ agonist improves neuronal insulin receptor function in hippocampus and brain mitochondria function in rats with insulin resistance induced by long term high-fat diets. Endocrinology. 2011; 153(1):329-38. DOI: 10.1210/en.2011-1502. View

13.

Krashes M, Shah B, Koda S, Lowell B . Rapid versus delayed stimulation of feeding by the endogenously released AgRP neuron mediators GABA, NPY, and AgRP. Cell Metab. 2013; 18(4):588-95. PMC: 3822903. DOI: 10.1016/j.cmet.2013.09.009. View

14.

Kitamura T, Feng Y, Ido Kitamura Y, Chua Jr S, Xu A, Barsh G . Forkhead protein FoxO1 mediates Agrp-dependent effects of leptin on food intake. Nat Med. 2006; 12(5):534-40. DOI: 10.1038/nm1392. View

15.

Ernst M, Wunderlich C, Hess S, Paehler M, Mesaros A, Koralov S . Enhanced Stat3 activation in POMC neurons provokes negative feedback inhibition of leptin and insulin signaling in obesity. J Neurosci. 2009; 29(37):11582-93. PMC: 6665760. DOI: 10.1523/JNEUROSCI.5712-08.2009. View

16.

Haas C, Kalinine E, Zimmer E, Hansel G, Brochier A, Oses J . Brain Insulin Administration Triggers Distinct Cognitive and Neurotrophic Responses in Young and Aged Rats. Mol Neurobiol. 2015; 53(9):5807-5817. DOI: 10.1007/s12035-015-9494-6. View

17.

Haskell-Luevano C, Chen P, Li C, Chang K, Smith M, Cameron J . Characterization of the neuroanatomical distribution of agouti-related protein immunoreactivity in the rhesus monkey and the rat. Endocrinology. 1999; 140(3):1408-15. DOI: 10.1210/endo.140.3.6544. View

18.

Seoane L, Lopez M, Tovar S, Casanueva F, Senaris R, Dieguez C . Agouti-related peptide, neuropeptide Y, and somatostatin-producing neurons are targets for ghrelin actions in the rat hypothalamus. Endocrinology. 2003; 144(2):544-51. DOI: 10.1210/en.2002-220795. View

19.

Karren M, Coonrod E, Anderson T, Shaw J . The role of Fis1p-Mdv1p interactions in mitochondrial fission complex assembly. J Cell Biol. 2005; 171(2):291-301. PMC: 2171191. DOI: 10.1083/jcb.200506158. View

20.

Kim I, Rodriguez-Enriquez S, Lemasters J . Selective degradation of mitochondria by mitophagy. Arch Biochem Biophys. 2007; 462(2):245-53. PMC: 2756107. DOI: 10.1016/j.abb.2007.03.034. View