Periodic Reporting for period 4 - INTEGRATE (Central integration of metabolic and hedonic cues in metabolic health)
Período documentado: 2021-04-01 hasta 2021-09-30
These neuronal glucose-regulated circuits are so far very poorly characterized. Identifying there anatomical locations and functional diversity, and how they become deregulated in the pathogenesis of metabolic diseases may lead to novel therapeutic approaches to these conditions.
The goals of INTEGRATE are to identify, in two brain regions, glucose sensing neuronal populations that are activated by rise in glucose concentrations (glucose excited or GE neurons) or by development of hypoglycemia (glucose inhibited or GI neurons); to characterize the neuronal circuits they are involved in and define the various physiological responses they control such as secretion of the pancreatic islet hormones insulin and glucagon, which control blood glucose levels, and the hedonic aspect of feeding behavior.
Thus, our work provides a mechanistic understanding of how glucose detection by VMN neuronal subpopulations that control distinct physiological responses, and which neuronal pathways these glucose responsive neurons are integrated in to control glucose homeostasis responses or motivated and context-dependent feeding behavior.
We also investigated the role of glucose responsive neurons of the paraventricular thalamic area (PVT). This region integrates signals related to body glucose and energy stores with the control of motivated feeding behavior. We characterized two populations of neurons, one that expresses the glucose transporter Glut2 and which is activated by hypoglycemia (GI neurons). The other expresses the glycolysis enzyme glucokinase and contains mostly neurons activated by glucose (GE neurons). These two neuronal populations have opposite effects on feeding behavior: activation of the GI neurons stimulates sucrose seeking behavior whereas the GE neurons suppress feeding and decrease motivated sucrose seeking. We found that the glucokinase-expressing neurons of the PVT receive extensive inputs from the hypothalamus and send dense projections to regions involved in the hedonic control of food consumption (the reward system), but also of fear and anxiety, thereby supporting the role of these neurons as important relays between homeostatic signals transmitted through the hypothalamus and the hedonic control of feeding behavior directed by the reward system. They show that glucose sensing by PVT neurons acts as a modulator of the integrative role of the PVT neurons.
We also performed a genetic analysis in mice to identify hypothalamic genes involved in the regulation of glucagon secretion, the hormone that restores normoglycemia in case of hypoglycemic episodes. This response is defective in a large proportion of diabetic patients treated with insulin and the normal mechanisms of hypoglycemia detection and how they fail in these patients are still very poorly characterized. Our genetic screen identified four genes, expressed in different neuronal populations, which all contribute to the normal glucagon response to hypoglycemia by different mechanisms that are still being fully deciphered. Nevertheless, our studies indicate that hypoglycemia detection by the brain relies on a complex, distributed hypoglycemia sensing system. This new information may provide novel ways to prevent hypoglycemic episodes in diabetic patients.
Globally, our data provide much new information about the complexity of neuronal glucose sensing, how these neurons control the activity of a variety of circuits involved in glucose homeostasis and in the integration of homeostatic and hedonic signals to control feeding. They provide a molecular entry point to further study the mechanisms of hypoglycemia sensing and their deregulations in insulin treated diabetic patients.