The role of brain insulin and leptin action in modulating hepatic triglyceride secretion

Hepatosteatosis and dyslipidemia are both hallmarks of the metabolic syndrome and plasma triglycerides (TG) correlate with insulin resistance (IR). Since hepatic lipogenesis is increased in the IR state, also known as the insulin paradox, TG secretion must not be too low in order to prevent steatosis. Insulin action comprises of direct effects on peripheral organs e.g. liver and the adipose tissue, but also of indirect effects that are mediated via the central nervous system (CNS). Systemic insulin decreases very low-density lipoprotein (VLDL) production by the liver, yet it is unknown whether brain insulin can independently regulate VLDL flux. Besides insulin, leptin, an adipocyte-derived anorexic hormone that circulates proportional to body fat, may also be implicated in regulating hepatic lipid load. Notably, leptin-deficient humans suffering from a rare condition called lipodystrophy develop marked fatty liver disease, which can be dramatically ameliorated by leptin treatment. Conversely, blocking leptin signaling in the brain leads to hepatic lipid accumulation in rodents, which is independent of changes in food intake. Similar to insulin, it is again unknown whether leptin can modulate VLDL secretion via CNS signaling. Here, we plan to study the role of brain insulin and leptin signaling on hepatic VLDL secretion by performing a series of tyloxapol infusion studies in conscious, non-restrained male Sprague Dawley rats during systemic or isolated brain hyperinsulinemia as well as isolated brain hyperleptinemia. The latter two conditions will be accomplished by continuously infusing insulin or leptin via pre-implanted stereotaxic cannulae targeting the 3rd ventricle. In addition, we will combine these stereotaxic infusion studies with isotope tracer dilution techniques in order to assess in vivo VLDL flux. Furthermore, we will assess the chronic effects of inducing or blocking brain insulin or leptin signaling on hepatic lipid content by non-invasively measuring liver fat over time using 1H-magnetic-resonance spectroscopy. We plan to complement the pharmacological experiments with selected genetic knock-out mouse models that allow specific ablation of the insulin receptors in the brain and/or peripheral organs. Finally, we plan to explore the contribution of brain insulin and leptin resistance in the dysregulation of triglyceride flux in metabolic disease. We speculate that the liver fat accumulation that is commonly seen in the obese state may be due to brain insulin and/or leptin resistance or in other words a failure to increase VLDL export from the liver in order to compensate for the caloric excess and unrestrained hepatic de novo lipogenesis in the insulin resistant state.

New signalling-pathways in the fight against obesity-related fatty liver disease identified Insulin Our research describes novel functions of the hormone insulin in the central nervous system. Insulin is produced in the pancreatic islets and secreted into the bloodstream. Besides its classical functions to reduce blood sugar insulin can also cross the blood-brain-barrier to bind brain insulin receptors. Our findings, which were published in the internationally-recognized journal Diabetes, show that the insulin signal in the brain protects non-adipose tissue organs, such as the liver, from exceeding fat accumulation. This occurs via a signal, which is conveyed by the autonomic nervous system. Brain insulin action limits lipid flux to the liver by blocking fat depletion and increases hepatic fat export thereby protecting from fatty liver disease. Conversely, a blockade of brain insulin signaling leads to a fatty liver. Based on these findings potential future drug-targets to treat fatty liver disease could be identified. Leptin Leptin is a hormone produced by the adipose tissue and critically involved in controlling appetite and hunger. Leptin passes the blood-brain-barrier and signals to the brain how much fat mass is available in the body. People suffering from pathological overweight (obesity) or a fatty liver, generally exhibit elevated circulating leptin levels due to an increase in body fat mass. However, the leptin signal arriving in the brain may be limited due to leptin resistance. Our study, published in the Top Journal Nature Communications, shows in rodent models that a direct activation of leptin receptors in the brain stem regulate the fat content of the liver via a vagal mechanism. The vagal nerve connects the brain with various organs and regulates metabolism. It is a part of the autonomous nervous system through which the central nervous system communicates with the organs. The binding of leptin to receptors expressed in the brain stem causes the activation of the vagal nerve and, consequently, the increase of the hepatic triglyceride export (dietary fat) and a reduction of de novo lipogenesis (synthesis of fat from carbohydrates) in the liver. Taken together leptin and insulin protect against a fatty liver by transmitting signals via a brain-vagus-liver axis thereby animating the liver to export fat. In people with obesity, leptin and insulin do not arrive at the brain in sufficient quantities to transmit the necessary signals to the liver for the export of lipids. One possible starting point for future therapies would be the direct administration of leptin and/or insulin into the brain thereby circumnavigating the blood-brain-barrier. This could be achieved by administering leptin/insulin via a nasal spray or pharmacological approaches which restore and/or improve brain leptin/insulin sensitivity. Translational research projects now have to clarify whether these results are also applicable in humans.