Hypothalamic ventromedial COUP-TFII protects against hypoglycemia-associated autonomic failure

Abstract

The nuclear receptor Chicken Ovalbumin Upstream Promoter-Transcription Factor II (COUP-TFII) is an important coordinator of glucose homeostasis through its function in different organs such as the endocrine pancreas, adipose tissue, skeletal muscle, and liver. Recently we have demonstrated that COUP-TFII expression in the hypothalamus is restricted to a subpopulation of neurons expressing the steroidogenic factor 1 transcription factor, known to play a crucial role in glucose homeostasis. To understand the functional significance of COUP-TFII expression in the steroidogenic factor 1 neurons, we generated hypothalamic ventromedial nucleus-specific COUP-TFII KO mice using the cyclization recombination/locus of XoverP1 technology. The heterozygous mutant mice display insulin hypersensitivity and a leaner phenotype associated with increased energy expenditure and similar food intake. These mutant mice also present a defective counterregulation to hypoglycemia with altered glucagon secretion. Moreover, the mutant mice are more likely to develop hypoglycemia-associated autonomic failure in response to recurrent hypoglycemic or glucopenic events. Therefore, COUP-TFII expression levels in the ventromedial nucleus are keys in the ability to resist the onset of hypoglycemia-associated autonomic failure.H ypothalamic neurons are able to detect changes in the concentration of circulating hormones and nutrients and to relay this information into adaptive signals toward peripheral organs aimed at maintaining glucose homeostasis and energy balance. Among these neurons, several studies have shown that the steroidogenic factor 1 (SF1) expressing ones, which are restricted to the hypothalamic ventromedial nucleus (VMN), are important modulators of metabolic functions through their ability to detect variations of extracellular concentrations of glucose, insulin, leptin, and orexin to coordinate insulin/glucose homeostasis (1-5). The SF1 transcription factor itself is a key actor of energy homeostasis ,as SF1 knockout (KO) mice are obese (6). SF1 KO mice display an abnormal organization of the VMN, as SF1 is necessary for the terminal differentiation of the VMN neurons (7,8). SF1 itself directs a genetic program involved in energy homeostasis and leptin action in the VMN (9). Outside these functions, SF1 neurons are also part of the neurocircuitry involved in the counterregulatory response (CRR) to hypoglycemia. To prevent hypoglycemia, organisms have developed several survival mechanisms of CRR such as decreased insulin secretion and increased glucagon secretion to quickly reestablish euglycemia (10, 11). The decreased insulin secretion is a direct effect of hypoglycemia on the pancreatic β cells, while the other CRRs are mainly directed by the central nervous system and in part by the SF1 neurons (12)(13)(14). Overall the SF1 neuronal population is at the interface between sensing of glucose concentrations and modulation of insulin-dependent metabolism and energy homeostasis.Recently we have observed that Chicken Ovalbumin Upstre...

Abnormal Paraventricular Nucleus of Hypothalamus and Growth Retardation Associated with Loss of Nuclear Receptor Gene COUP-TFII

“…Consistent with a previous report 43 , the expression of COUP-TFII was readily detected in the majority of SF1 + VMH neurons at 1 M (Fig. 3A–D).…”

COUP-TFII in Health and Disease

“…The difference in insulin effects on COUP-TFII in the CNS compared to peripheral tissues are likely a consequence of insulin acting as an anabolic factor for the liver or the adipose tissue and catabolic in the central nervous system [81]. In agreement with this observation, COUP-TFII +/− mice in the ventromedial neurons display a liner phenotype, with increased energy expenditure, and are more prone to develop hypoglycemic-associated autonomic failure [82].…”

Sex-Specific Control of Fat Mass and Counterregulation by Hypothalamic Glucokinase

“…For some experiments, Rosa26tdtomato mice were bred with Gck lox/lox mice to generate Sf1-Cre;Rosa26-tdtomato;Gck +/+ and Sf1-Cre;Rosa-26tdtomato; Gck lox/lox mice. Sf1-Cre mice do not have a phenotype regarding body weight gain, adiposity, glucose homeostasis, or food intake (24,26,27).…”