ABSTRACT
Recent studies have shown that the hypothalamic neuropeptide 26RFa regulates glucose homeostasis by acting as an incretin and increasing insulin sensitivity. In this study, we further characterized the role of the 26RFa/GPR103 peptidergic system in the global regulation of glucose homeostasis using a 26RFa receptor antagonist and also assessed whether a dysfunction of the 26RFa/GPR103 system occurs in obese hyperglycemic mice. First, we demonstrate that administration of the GPR103 antagonist reduces the global glucose-induced incretin effect and insulin sensitivity whereas, conversely, administration of exogenous 26RFa attenuates glucose-induced hyperglycemia. Using a mouse model of high-fat diet-induced obesity and hyperglycemia, we found a loss of the antihyperglcemic effect and insulinotropic activity of 26RFa, accompanied with a marked reduction of its insulin-sensitive effect. Interestingly, this resistance to 26RFa is associated with a downregulation of the 26RFa receptor in the pancreatic islets, and insulin target tissues. Finally, we observed that the production and release kinetics of 26RFa after an oral glucose challenge is profoundly altered in the high-fat mice. Altogether, the present findings support the view that 26RFa is a key regulator of glucose homeostasis whose activity is markedly altered under obese/hyperglycemic conditions.
Subject(s)
Carbohydrate Metabolism/drug effects , Glucose/metabolism , Hyperglycemia/metabolism , Neuropeptides/pharmacology , Obesity/metabolism , Animals , Blood Glucose/drug effects , Blood Glucose/metabolism , Cells, Cultured , Glucose Tolerance Test , Homeostasis/drug effects , Humans , Hyperglycemia/complications , Insulin/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Obese , Neuropeptides/physiology , Obesity/complicationsABSTRACT
Human Immunodeficiency Virus (HIV) infection is associated with adrenal disorders, which must not be underestimated. Adrenal morphologic changes are primarily related to opportunistic infections, mostly by cytomegalovirus and mycobacteria, and malignant tumours such as non-Hodgkin's lymphoma and Kaposi's sarcoma. The most frequent biological alteration reported to date is the increases in cortisol concentrations which results from a decrease in cortisol metabolism and hyperactivity of the hypothalamo-pituitary-adrenal axis commonly referred to as pseudo-Cushing's syndrome. These modifications can be a consequence of antiretroviral therapy and do not require any investigation or specific treatment. Conversely, adrenal insufficiency, either iatrogenic or secondary to glandular infiltration by neoplasms or infections, needs long-term substitution with hydrocortisone, but at present occurs more rarely and usually at late stages of disease progression. The impact of HIV infection on the other adrenocortical functions has been less reported in the literature although several studies show low levels of adrenal androgens, especially dehydroepiandrostenedione (DHEA). Impairment in mineralocorticoid function appears occasional and remains a subject of debate.
