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Fgf15 Neurons of the Dorsomedial Hypothalamus Control Glucagon Secretion and Hepatic Gluconeogenesis
- Source :
- Diabetes, Diabetes, vol. 70, no. 7, pp. 1443-1457
- Publication Year :
- 2021
- Publisher :
- American Diabetes Association, 2021.
-
Abstract
- The counterregulatory response to hypoglycemia is an essential survival function. It is controlled by an integrated network of glucose-responsive neurons, which trigger endogenous glucose production to restore normoglycemia. The complexity of this glucoregulatory network is, however, only partly characterized. In a genetic screen of a panel of recombinant inbred mice we previously identified Fgf15, expressed in neurons of the dorsomedial hypothalamus (DMH), as a negative regulator of glucagon secretion. Here, we report on the generation of Fgf15 CretdTomato mice and their use to further characterize these neurons. We show that they were glutamatergic and comprised glucose-inhibited and glucose-excited neurons. When activated by chemogenetics, Fgf15 neurons prevented the increase in vagal nerve firing and the secretion of glucagon normally triggered by insulin-induced hypoglycemia. On the other hand, they increased the activity of the sympathetic nerve in the basal state and prevented its silencing by glucose overload. Higher sympathetic tone increased hepatic Creb1 phosphorylation, Pck1 mRNA expression, and hepatic glucose production leading to glucose intolerance. Thus, Fgf15 neurons of the DMH participate in the counterregulatory response to hypoglycemia by a direct adrenergic stimulation of hepatic glucose production while suppressing vagally induced glucagon secretion. This study provides new insights into the complex neuronal network that prevents the development of hypoglycemia.
- Subjects :
- Male
0301 basic medicine
medicine.medical_specialty
Sympathetic Nervous System
Endocrinology, Diabetes and Metabolism
Hypothalamus
030209 endocrinology & metabolism
Hypoglycemia
Glucagon
Mice
03 medical and health sciences
Glutamatergic
0302 clinical medicine
PCK1
Internal medicine
Internal Medicine
medicine
Biological neural network
Animals
Secretion
Cyclic AMP Response Element-Binding Protein
Neurons
Chemistry
Gluconeogenesis
Glucagon secretion
medicine.disease
Fibroblast Growth Factors
Mice, Inbred C57BL
Metabolism
030104 developmental biology
Endocrinology
Liver
Female
Subjects
Details
- ISSN :
- 1939327X and 00121797
- Volume :
- 70
- Database :
- OpenAIRE
- Journal :
- Diabetes
- Accession number :
- edsair.doi.dedup.....5ac7e8c6f696bbfb9c132d6843dbbbac