In Uncontrolled Diabetes, Hyperglucagonemia and Ketosis Result From Deficient Leptin Action in the Parabrachial Nucleus.

Abstract

Growing evidence implicates neurons that project from the lateral parabrachial nucleus (LPBN) to the hypothalamic ventromedial nucleus (VMN) in a neurocircuit that drives counterregulatory responses to hypoglycemia, including increased glucagon secretion. Among LPBN neurons in this circuit is a subset that expresses cholecystokinin (LPBNCCK neurons) and is tonically inhibited by leptin. Because uncontrolled diabetes is associated with both leptin deficiency and hyperglucagonemia, and because intracerebroventricular (ICV) leptin administration reverses both hyperglycemia and hyperglucagonemia in this setting, we hypothesized that deficient leptin inhibition of LPBNCCK neurons drives activation of this LPBN→VMN circuit and thereby results in hyperglucagonemia. Here, we report that although bilateral microinjection of leptin into the LPBN does not ameliorate hyperglycemia in rats with streptozotocin-induced diabetes mellitus (STZ-DM), it does attenuate the associated hyperglucagonemia and ketosis. To determine if LPBN leptin signaling is required for the antidiabetic effect of ICV leptin in STZ-DM, we studied mice in which the leptin receptor was selectively deleted from LPBNCCK neurons. Our findings show that although leptin signaling in these neurons is not required for the potent antidiabetic effect of ICV leptin, it is required for leptin-mediated suppression of diabetic hyperglucagonemia. Taken together, these findings suggest that leptin-mediated effects in animals with uncontrolled diabetes occur through actions involving multiple brain areas, including the LPBN, where leptin acts specifically to inhibit glucagon secretion and associated ketosis.

• Authors: Thomas H Meek, Miles E Matsen, Chelsea L Faber, Colby L Samstag, Vincent Damian, Hong T Nguyen, Jarrad M Scarlett, Jonathan N Flak, Martin G Myers Jr, Gregory J Morton
• Journal: Endocrinology (Endocrinology) Vol. 159 Issue 4 Pg. 1585-1594 (04 01 2018) ISSN: 1945-7170 [Electronic] United States
• PMID: 29438473 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Blood Glucose
• Insulin
• Leptin
• Glucagon

Topics

• Animals
• Blood Glucose
• Diabetes Mellitus, Experimental (metabolism)
• Glucagon (blood)
• Injections, Intraventricular
• Insulin (blood)
• Ketosis (metabolism)
• Leptin (pharmacology)
• Male
• Mice
• Neurons (drug effects, metabolism)
• Parabrachial Nucleus (drug effects, metabolism)
• Rats
• Rats, Wistar
• Signal Transduction (drug effects)