Paraventricular Hypothalamus Mediates Diurnal Rhythm of Metabolism

Overview

Journal Nat Commun

Specialty Biology

Date 2020 Aug 1

PMID 32732906

Citations 27

Authors

Eun Ran Kim

Yuanzhong Xu

Ryan M Cassidy

Yungang Lu

Yongjie Yang

Jinbin Tian

De-Pei Li

Rachel Van Drunen

Aleix Ribas-Latre

Zhao-Lin Cai

Mingshan Xue

Benjamin R Arenkiel

Kristin Eckel-Mahan

Yong Xu

Qingchun Tong

Affiliations

Soon will be listed here.

Abstract

Defective rhythmic metabolism is associated with high-fat high-caloric diet (HFD) feeding, ageing and obesity; however, the neural basis underlying HFD effects on diurnal metabolism remains elusive. Here we show that deletion of BMAL1, a core clock gene, in paraventricular hypothalamic (PVH) neurons reduces diurnal rhythmicity in metabolism, causes obesity and diminishes PVH neuron activation in response to fast-refeeding. Animal models mimicking deficiency in PVH neuron responsiveness, achieved through clamping PVH neuron activity at high or low levels, both show obesity and reduced diurnal rhythmicity in metabolism. Interestingly, the PVH exhibits BMAL1-controlled rhythmic expression of GABA-A receptor γ2 subunit, and dampening rhythmicity of GABAergic input to the PVH reduces diurnal rhythmicity in metabolism and causes obesity. Finally, BMAL1 deletion blunts PVH neuron responses to external stressors, an effect mimicked by HFD feeding. Thus, BMAL1-driven PVH neuron responsiveness in dynamic activity changes involving rhythmic GABAergic neurotransmission mediates diurnal rhythmicity in metabolism and is implicated in diet-induced obesity.

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References

Bechtold D, Loudon A . Hypothalamic clocks and rhythms in feeding behaviour. Trends Neurosci. 2013; 36(2):74-82. DOI: 10.1016/j.tins.2012.12.007. View

Mohawk J, Green C, Takahashi J . Central and peripheral circadian clocks in mammals. Annu Rev Neurosci. 2012; 35:445-62. PMC: 3710582. DOI: 10.1146/annurev-neuro-060909-153128. View

Colwell C . Linking neural activity and molecular oscillations in the SCN. Nat Rev Neurosci. 2011; 12(10):553-69. PMC: 4356239. DOI: 10.1038/nrn3086. View

SATINOFF E, Prosser R . Suprachiasmatic nuclear lesions eliminate circadian rhythms of drinking and activity, but not of body temperature, in male rats. J Biol Rhythms. 1988; 3(1):1-22. DOI: 10.1177/074873048800300101. View

Turek F, Joshu C, Kohsaka A, Lin E, Ivanova G, McDearmon E . Obesity and metabolic syndrome in circadian Clock mutant mice. Science. 2005; 308(5724):1043-5. PMC: 3764501. DOI: 10.1126/science.1108750. View

Yang S, Liu A, Weidenhammer A, Cooksey R, McClain D, Kim M . The role of mPer2 clock gene in glucocorticoid and feeding rhythms. Endocrinology. 2009; 150(5):2153-60. PMC: 2671901. DOI: 10.1210/en.2008-0705. View

Gatfield D, Schibler U . Circadian glucose homeostasis requires compensatory interference between brain and liver clocks. Proc Natl Acad Sci U S A. 2008; 105(39):14753-4. PMC: 2567439. DOI: 10.1073/pnas.0807861105. View

Kohsaka A, Laposky A, Ramsey K, Estrada C, Joshu C, Kobayashi Y . High-fat diet disrupts behavioral and molecular circadian rhythms in mice. Cell Metab. 2007; 6(5):414-21. DOI: 10.1016/j.cmet.2007.09.006. View

Hood S, Amir S . The aging clock: circadian rhythms and later life. J Clin Invest. 2017; 127(2):437-446. PMC: 5272178. DOI: 10.1172/JCI90328. View

10.

Hatori M, Vollmers C, Zarrinpar A, DiTacchio L, Bushong E, Gill S . Time-restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high-fat diet. Cell Metab. 2012; 15(6):848-60. PMC: 3491655. DOI: 10.1016/j.cmet.2012.04.019. View

11.

Chaix A, Zarrinpar A, Miu P, Panda S . Time-restricted feeding is a preventative and therapeutic intervention against diverse nutritional challenges. Cell Metab. 2014; 20(6):991-1005. PMC: 4255155. DOI: 10.1016/j.cmet.2014.11.001. View

12.

van der Klaauw A, Farooqi I . The hunger genes: pathways to obesity. Cell. 2015; 161(1):119-132. DOI: 10.1016/j.cell.2015.03.008. View

13.

Sandoval D, Cota D, Seeley R . The integrative role of CNS fuel-sensing mechanisms in energy balance and glucose regulation. Annu Rev Physiol. 2007; 70:513-35. DOI: 10.1146/annurev.physiol.70.120806.095256. View

14.

Sutton A, Myers Jr M, Olson D . The Role of PVH Circuits in Leptin Action and Energy Balance. Annu Rev Physiol. 2016; 78:207-21. PMC: 5087283. DOI: 10.1146/annurev-physiol-021115-105347. View

15.

Atasoy D, Betley J, Su H, Sternson S . Deconstruction of a neural circuit for hunger. Nature. 2012; 488(7410):172-7. PMC: 3416931. DOI: 10.1038/nature11270. View

16.

Wu Z, Ran Kim E, Sun H, Xu Y, Mangieri L, Li D . GABAergic projections from lateral hypothalamus to paraventricular hypothalamic nucleus promote feeding. J Neurosci. 2015; 35(8):3312-8. PMC: 4339348. DOI: 10.1523/JNEUROSCI.3720-14.2015. View

17.

Mangieri L, Lu Y, Xu Y, Cassidy R, Xu Y, Arenkiel B . A neural basis for antagonistic control of feeding and compulsive behaviors. Nat Commun. 2018; 9(1):52. PMC: 5754347. DOI: 10.1038/s41467-017-02534-9. View

18.

Liu T, Kong D, Shah B, Ye C, Koda S, Saunders A . Fasting activation of AgRP neurons requires NMDA receptors and involves spinogenesis and increased excitatory tone. Neuron. 2012; 73(3):511-22. PMC: 3278709. DOI: 10.1016/j.neuron.2011.11.027. View

19.

Ran Kim E, Wu Z, Sun H, Xu Y, Mangieri L, Xu Y . Hypothalamic Non-AgRP, Non-POMC GABAergic Neurons Are Required for Postweaning Feeding and NPY Hyperphagia. J Neurosci. 2015; 35(29):10440-50. PMC: 4510285. DOI: 10.1523/JNEUROSCI.1110-15.2015. View

20.

Zhang X, van den Pol A . Hypothalamic arcuate nucleus tyrosine hydroxylase neurons play orexigenic role in energy homeostasis. Nat Neurosci. 2016; 19(10):1341-7. PMC: 6402046. DOI: 10.1038/nn.4372. View