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Brain glucose metabolism controls the hepatic secretion of triglyceride-rich lipoproteins

Nature Medicine volume 13, pages 171–180 (2007)Cite this article

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Abstract

Increased production of very low-density lipoprotein (VLDL) is a critical feature of the metabolic syndrome. Here we report that a selective increase in brain glucose lowered circulating triglycerides (TG) through the inhibition of TG-VLDL secretion by the liver. We found that the effect of glucose required its conversion to lactate, leading to activation of ATP-sensitive potassium channels and to decreased hepatic activity of stearoyl-CoA desaturase-1 (SCD1). SCD1 catalyzed the synthesis of oleyl-CoA from stearoyl-CoA. Curtailing the liver activity of SCD1 was sufficient to lower the hepatic levels of oleyl-CoA and to recapitulate the effects of central glucose administration on VLDL secretion. Notably, portal infusion of oleic acid restored hepatic oleyl-CoA to control levels and negated the effects of both central glucose and SCD1 deficiency on TG-VLDL secretion. These central effects of glucose (but not those of lactate) were rapidly lost in diet-induced obesity. These findings indicate that a defect in brain glucose sensing could play a critical role in the etiology of the metabolic syndrome.

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Figure 1: Brain glucose metabolism lowers plasma triglycerides.
Figure 2: Effect of central glucose metabolism on VLDL secretion.
Figure 3: Brain glucose metabolism inhibits hepatic SCD1 activity.
Figure 4: Effect of hepatic SCD1 activity and oleyl-CoA on VLDL secretion.
Figure 5: Brain glucose, but not lactate, administration does not inhibit plasma triglyceride levels and hepatic VLDL secretion in overfed rats.
Figure 6: Hypothalamic sensing of circulating lactate is required to inhibit hepatic TG-VLDL secretion.

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  • 18 April 2007

    In the version of this article initially published on-line, it was not indicated that the first two authors (T.K.T. L. and R.G.-J.) contributed equally to this work. The error has been corrected in the HTML and PDF versions of the article.

Notes

  1. *NOTE: Nat. Med. 13, 171-180 (2007); published online 4 February 2007; corrected after print 18 April 2007. In the version of this article initially published on-line, it was not indicated that the first two authors (T.K.T. L. and R.G.-J.) contributed equally to this work. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank C. Baveghems and B. Liu for technical assistance. This work was supported by grants from the US National Institutes of Health (DK45024, DK48321 and AG 21654 to L.R.; DK47208 to G.J.S.) and the Albert Einstein College of Medicine Diabetes Research and Training Center (DK 20541). T.K.T.L. was supported by a fellowship from the US National Institutes of Health (F32-DK072876) and is currently appointed as the John Kitson McIvor Endowed Chair in Diabetes Research at the University Health Network and University of Toronto.

Author information

Author notes

  1. Tony K T Lam

    Present address: Present address: Departments of Physiology and Medicine, University Health Network and University of Toronto, Toronto M5G 1L7, Canada,

  2. Tony K T Lam and Roger Gutierrez-Juarez: These authors contributed equally to this work

Authors and Affiliations

  1. Departments of Medicine and Molecular Pharmacology, Diabetes Research Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, 10461, New York, USA

    Tony K T Lam, Roger Gutierrez-Juarez, Alessandro Pocai, Gary J Schwartz & Luciano Rossetti

  2. ISIS Pharmaceuticals, 1896 Rutherford Road, Carlsbad, 92008, California, USA

    Sanjay Bhanot

  3. Department of Pathology, University of Cincinnati, 2120 East Galbraith Road, Cincinnati, 45237, Ohio, USA

    Patrick Tso

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Contributions

T.K.T.L and R.G.-J. conducted the experiments and data analyses, and wrote the manuscript; A.P. conducted the experiments; S.B. provided the SCD1 antisense oligodeoxynucleotide; P.T. performed the Apo100/48 and TG content determination in HPLC fractions; G.J.S. performed the selective hepatic branch vagotomy; L.R. supervised the project and wrote the manuscript.

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Correspondence to Luciano Rossetti.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

A dose-response curve of hypothalamic and plasma glucose concentrations. (PDF 207 kb)

Supplementary Fig. 2

The rate of appearance of total (small + medium + large) VLDL particles was not different among groups. (PDF 230 kb)

Supplementary Fig. 3

ApoB100/48 secretion in 10h fasted rats. (PDF 372 kb)

Supplementary Fig. 4

Effect of ICV glucose on TG-VLDL secretion in 5h and 10h fasted rats. (PDF 229 kb)

Supplementary Fig. 5

Effect of HFD in male Wistar and Sprague Dawley rats. (PDF 246 kb)

Supplementary Table 1

Characteristics of the groups during the central glucose administration. (PDF 3 kb)

Supplementary Table 2

Characteristics of the groups during central lactate administration. (PDF 3 kb)

Supplementary Table 3

Diet Composition (PDF 2 kb)

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Lam, T., Gutierrez-Juarez, R., Pocai, A. et al. Brain glucose metabolism controls the hepatic secretion of triglyceride-rich lipoproteins. Nat Med 13, 171–180 (2007). https://doi.org/10.1038/nm1540

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