Small molecule glucokinase activators disturb lipid homeostasis and induce fatty liver in rodents: a warning for therapeutic applications in humans.

Background And Purpose: Small-molecule glucokinase activators (GKAs) are currently being investigated as therapeutic options for the treatment of type 2 diabetes (T2D). Because liver overexpression of glucokinase is thought to be associated with altered lipid profiles, this study aimed at assessing the potential lipogenic risks linked to oral GKA administration.

Experimental Approach: Nine GKA candidates were qualified for their ability to activate recombinant glucokinase and to stimulate glycogen synthesis in rat hepatocytes and insulin secretion in rat INS-1E cells.

Aging and obesity induce distinct gene expression adaptation in the liver of C57BL/6J mice.

Background: Aging and obesity induce complex transcriptomic changes in the liver, promoting the development of insulin resistance and type 2 diabetes. In spite of an increasing amount of studies on the role of aging and nutrient excess in metabolic disorders, the specific molecular events leading to insulin resistance are still poorly understood.

Methods: This study presents a comparative analysis of hepatic gene expression profiles between young adult C57BL/6J mice fed with a low- or a high-fat diet for 1 and 12 months.

Peripheral ghrelin interacts with orexin neurons in glucostatic signalling.

Ghrelin interactions with glycemia in appetite control as well as the potential mechanisms involving the orexin and melanin-concentrating hormone (MCH) neurons in the orexigenic ghrelin signals were investigated by using a specific anti-ghrelin antibody (AGA). Our results confirm that peripheral ghrelin is an important signal in meal initiation and appetite. Employing immunohistochemistry techniques, we found that c-fos positive neurons in the lateral hypothalamus (LH) and perifornical area (PFA) increased after insulin or 2-deoxyglucose administration.

The nucleus tractus solitari (NTS) participates in peripheral ghrelin glucostatic hunger signalling mediated by insulin.

Three extrahypothalamic areas, the nucleus of the tractus solitari (NTS), the central nucleus of the amygdala (CeA) and the dorsal raphe nucleus (DRN), all potentially involved in peripheral ghrelin signalling of appetite control mediated by the glucose levels were examined. Thus, a specific anti-ghrelin antibody (AGA) was intravenously administered in order to remove the ghrelin signalling and then, subsequently, 4-h food intake, plasma glucose levels and the brain c-fos expression in the NTS, CeA and DRN were assessed. Food intake significantly decreased when the AGA was administered.

Peripheral ghrelin participates in glucostatic feeding mechanisms and in the anorexigenic signalling mediated by CART and CRF neurons.

Ghrelin is upregulated under negative energy balance conditions, including starvation and hypoglycemia, while it is downregulated under situations of positive energy balance, such as feeding, hyperglycemia and obesity. The aims of this study were to assess potential ghrelin interactions with glucose levels in appetite control and to identify potential mechanisms involving orexigenic and anorexigenic ghrelin mediated signals by using a specific anti-ghrelin antibody. Our results confirm that peripheral ghrelin is an important signal in meal initiation and food intake stimulation.