Control of Physiologic Glucose Homeostasis via the Hypothalamic Modulation of Gluconeogenic Substrate Availability

Hashsham, A.; Kodur, N.; Su, J.; Tomlinson, A. J.; Yacawych, W. T.; Flak, J. N.; Lewis, K. T.; Oles, L. R.; Mori, H.; Bozadjieva-Kramer, N.; Turcu, A. F.; MacDougald, O. A.; Myers, M. G.; Affinati, A. H.

doi:10.1101/2024.05.20.594873

bioRxiv · 10.1101/2024.05.20.594873

Control of Physiologic Glucose Homeostasis via the Hypothalamic Modulation of Gluconeogenic Substrate Availability

Hashsham, A.·Kodur, N.·Su, J.·Tomlinson, A. J.·Yacawych, W. T.·Flak, J. N.·Lewis, K. T.·Oles, L. R.·Mori, H.·Bozadjieva-Kramer, N.·Turcu, A. F.·MacDougald, O. A.·Myers, M. G.·Affinati, A. H.

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Abstract

The brain augments glucose production during fasting, but the mechanisms are poorly understood. Here, we show that Cckbr-expressing neurons in the ventromedial hypothalamic nucleus (VMNCckbr cells) prevent low blood glucose during fasting through sympathetic nervous system (SNS)-mediated augmentation of adipose tissue lipolysis and substrate release. Activating VMNCckbr neurons mobilized gluconeogenic substrates without altering glycogenolysis or gluconeogenic enzyme expression. Silencing these cells (CckbrTetTox animals) reduced fasting blood glucose, impaired lipolysis, and decreased circulating glycerol (but not other gluconeogenic substrates) despite normal insulin, counterregulatory hormones, liver glycogen, and liver gluconeogenic gene expression. Furthermore, {beta}3-adrenergic adipose tissue stimulation in CckbrTetTox animals restored lipolysis and blood glucose. Hence, VMNCckbr neurons impact blood glucose not by controlling islet or liver physiology, but rather by mobilizing gluconeogenic substrates. These findings establish a central role for hypothalamic and SNS signaling during normal glucose homeostasis and highlight the importance of gluconeogenic substrate mobilization during physiologic fasting.

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Hashsham, A., Kodur, N., Su, J., Tomlinson, A. J., Yacawych, W. T., Flak, J. N., Lewis, K. T., Oles, L. R., Mori, H., Bozadjieva-Kramer, N., Turcu, A. F., MacDougald, O. A., Myers, M. G., Affinati, A. H.. 2024-05-21. Control of Physiologic Glucose Homeostasis via the Hypothalamic Modulation of Gluconeogenic Substrate Availability. https://doi.org/10.1101/2024.05.20.594873

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