This project is based upon our recently published evidence that the brain can rapidly, potently and selectively increase insulin-independent glucose lowering (referred to as """"""""glucose effectiveness,"""""""" or GE). The overarching goals are to employ state-of-the-art methods in defined mouse models that allow us to identify neurocircuitry underlying this effect, investigate their physiological relevance, and determine if defects in this CNS control system contribute to reduced GE and glucose intolerance in diet-induced obesity (DIO). We propose two specific aims:
Specific Aim 1. To identify neurons regulating GE and determine their physiological role in glucose homeostasis. We will use Minimal Model analysis of glucose and insulin data from a frequently sampled intravenous glucose tolerance test (FSIGT) to measure insulin secretion, insulin sensitivity and GE. Proposed studies will 1) test a model of discrete neuronal subsets in hypothalamus and hindbrain proposed to mediate the actions of leptin and FGF19 to increase GE, and 2) determine if glucose intolerance results when the function of these neurocircuits is impaired.
Specific Aim 2. To determine if neuronal control of GE is impaired in diet-induced obesity (DIO). Studies will be conducted in mice with DIO to determine 1) if reduced GE and glucose intolerance can be ameliorated by manipulating the activity of specified neurons that comprise the neurociruitry controlling GE, and 2) whether these neurons are targets of obesity-associated gliosis and neuron injury. By expanding our understanding of the role of the brain in the control of GE in normal and obese mice, these studies will shed new light on the pathogenesis of glucose intolerance and diabetes and inform future approaches to the treatment of these disorders.
The escalating epidemic of obesity and type 2 diabetes represents one of the most pressing and costly biomedical challenges confronting modern society, yet much about the pathogenesis of these disorders remains unknown. This proposal is based upon evidence of a previously unrecognized role for the brain in glucose homeostasis involving regulatory mechanisms that overlap with and complement those of properly functioning pancreatic islets. By delineating these central mechanisms, our studies will lay the groundwork for future therapies that may be needed if we are to more effectively confront the diabetes epidemic.
|Faber, Chelsea L; Matsen, Miles E; Velasco, Kevin R et al. (2018) Distinct Neuronal Projections From the Hypothalamic Ventromedial Nucleus Mediate Glycemic and Behavioral Effects. Diabetes 67:2518-2529|
|Bentsen, Marie Aare; Mirzadeh, Zaman; Schwartz, Michael W (2018) Revisiting How the Brain Senses Glucose-And Why. Cell Metab :|
|Dorfman, Mauricio D; Krull, Jordan E; Scarlett, Jarrad M et al. (2017) Deletion of Protein Kinase C ? in POMC Neurons Predisposes to Diet-Induced Obesity. Diabetes 66:920-934|
|Campos, Carlos A; Bowen, Anna J; Han, Sung et al. (2017) Cancer-induced anorexia and malaise are mediated by CGRP neurons in the parabrachial nucleus. Nat Neurosci 20:934-942|
|Deem, Jennifer D; Muta, Kenjiro; Scarlett, Jarrad M et al. (2017) How Should We Think About the Role of the Brain in Glucose Homeostasis and Diabetes? Diabetes 66:1758-1765|
|Schwartz, Michael W; Seeley, Randy J; Zeltser, Lori M et al. (2017) Obesity Pathogenesis: An Endocrine Society Scientific Statement. Endocr Rev 38:267-296|
|Morton, Gregory J; Muta, Kenjiro; Kaiyala, Karl J et al. (2017) Evidence That the Sympathetic Nervous System Elicits Rapid, Coordinated, and Reciprocal Adjustments of Insulin Secretion and Insulin Sensitivity During Cold Exposure. Diabetes 66:823-834|
|Meek, Thomas H; Nelson, Jarrell T; Matsen, Miles E et al. (2016) Functional identification of a neurocircuit regulating blood glucose. Proc Natl Acad Sci U S A 113:E2073-82|
|Scarlett, Jarrad M; Rojas, Jennifer M; Matsen, Miles E et al. (2016) Central injection of fibroblast growth factor 1 induces sustained remission of diabetic hyperglycemia in rodents. Nat Med 22:800-6|
|Campos, Carlos A; Bowen, Anna J; Schwartz, Michael W et al. (2016) Parabrachial CGRP Neurons Control Meal Termination. Cell Metab 23:811-20|
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