Central integration of metabolic and hedonic cues in metabolic health

The control of blood glucose levels and of feeding behavior depends on the activity of intricate brain neuronal circuits. Blood glucose concentrations can directly modulate the activity of some of these neurons. Glucose, thus, acts as a signal to regulate its own homeostasis; it also regulates eating behavior. Deregulation of these central glucose sensing neurons may lead to metabolic diseases such as obesity and type 2 diabetes as well as bulimia or anorexia.

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.

We have been working on two specific brain areas. One is the ventromedial nucleus of the hypothalamus (VMN), a region known to have multiple effects on the homeostatic (automatic) regulation of blood glucose concentrations and of feeding behavior. We showed that the activity of GI neurons of the VMN depends on the activity of the enzyme (AMP-kinase), which is an evolutionary conserved metabolic sensor activated, in particular, by hypoglycemia. We showed that AMP-kinase controls the expression of an enzyme (Txn2), expressed in mitochondria, and which protects GI neurons against the oxidative stress that is generated by hypoglycemia; we found that expression of Txn2 in neurons lacking AMP-kinase was sufficient to restore the function of GI neurons. In the VMN, we also identified a population of GE neurons, which send projection to a distinct brain region (the Lateral Septum) and which suppress feeding by inducing an avoidance and flight response.

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.

Over the course of INTEGRATE, we have generated important new data pertaining to 1) the mechanisms of hypoglycemia detection by neurons of the hypothalamus; 2) how these hypoglycemia sensing neurons are integrated in a general circuits that control glucagon secretion; 3) how a subpopulation of hyperglycemia activated neurons of the VMN control motivated feeding behavior through specific projection to a particular brain area, the lateral septum; 4) the contrasting roles of two subpopulations of neurons of the paraventricular thalamus which are activated either by hypoglycemia or hyperglycemia and which, respectively, increase or suppress motivated feeding behavior through their connections to the reward system. 5) In genetic screens for novel genes controlling hypoglycemia-induced glucagon secretion – an essential survival response that restores normoglycemia – we identified four genes that act in separate cellular populations of the central nervous system to a modulate glucagon secretion and hepatic glucose production to preserve normoglycemia.
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.

Periodic Reporting for period 4 - INTEGRATE (Central integration of metabolic and hedonic cues in metabolic health)

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