Participating groups

Roberto Coppari

Hundreds of millions are affected by at least one type of metabolic dysfunction. Obesity and diabetes mellitus type I and II are the most common metabolic diseases. Unfortunately, the prevalence of obesity and diabetes mellitus type I and II is also increasing at alarming annual rates worldwide. Thus, the already-high number of obese and diabetic subjects is projected to increase significantly in the following years.

Obesity develops when energy intake consistently exceeds energy output. Diabetes Mellitus Type II is a condition displaying chronic hyperglycemia, hyperinsulinemia and hypertriglyceridemia. While obesity and diabetes type II are often associated with each other, the molecular mechanisms linking these two illnesses are still obscure. To date, effective, long-lasting anti-obesity pharmacological treatments are lacking. Also, the distinct and refractory responses to currently-available drugs used against diabetes type II and the discovery of polymorphisms in several genes associated with this condition suggest that this disease is heterogeneous in respect to primary dysfunctions. Effective treatments against obesity and diabetes type II are therefore urgently needed. To these ends, we will need to better understand i) the cellular mechanisms and neuronal pathways controlling energy and glucose homeostasis, and ii) the primary defects causing energy and/or glucose imbalance. In the laboratory, we are currently assessing whether metabolic-sensor proteins (i.e.: proteins that link the status of energy availability with cellular gene expression, activity and fate) in hypothalamic and caudal brainstem neurons exert critical roles for maintaining energy and glucose balance. A working hypothesis is that defects in neuronal metabolic-sensing mechanisms play an important, primary pathogenic role in the development of obesity and diabetes type II. To directly test our hypotheses, we are currently assessing the metabolic outcomes of genetically-mediated deletion or overexpression of metabolic-sensor proteins (e.g.: SIRT1, SIRT6, KATP-channels) only in restricted neuronal groups (e.g.: POMC-, AgRP-, SF1-, SIM1-, Phox2b-, or ChAT-expressing neurons) in mice.

Diabetes Mellitus Type I occurs as a consequence of pancreatic β-cells loss; a defect that leads to hyperglycemia, hyperglucagonemia, cachexia, ketoacidosis. This disease is deadly if untreated. Currently, the only life-saving intervention available for people affected by diabetes mellitus type I is insulin therapy. However, even with this therapy, complications of diabetes type I include debilitating and long-lasting conditions as for example heart disease, neuropathy, and hypertension. Moreover, probably owing to insulin’s lipogenic and cholesterologenic actions, long-term insulin treatment is suspected to underlie the increased incidence of coronary artery disease (>90% after the age of 55 year) seen in type I diabetic subjects. Furthermore, in part due to insulin’s potent, fast-acting, glycemia-lowering effects, intensive insulin therapy significantly increases the risk of hypoglycemia, an event that is disabling and can even be fatal. Therefore, despite remarkable life-saving actions, insulin therapy does not restore metabolic homeostasis and may even lead to serious side effects (e.g.: coronary artery disease and hypoglycemia). Because of the aforementioned reasons, better approaches for the management of diabetes type I are urgently needed. In the laboratory, using rodents affected by diabetes mellitus type I as model organism, we have gathered evidences supporting that the hormone leptin exerts superior anti-diabetic actions compared to insulin. We are currently making use of genetically-engineered mice expressing leptin receptors only in selected neuronal groups to genetically dissect the pathways by which leptin monotherapy greatly improves diabetes type I. Results from these studies will lead to the identification of i) neuropeptide(s) and/or neurotransmitter(s) secreted by critical pre- and/or post-ganglionic neurons and/or ii) circulating factor(s) underlying leptin’s beneficial actions in the context of diabetes type I.

In summary, to directly test our hypotheses we combine studies on hypothalamic organotypic slice cultures, electrophysiological assays and physiological studies of genetically-engineered mice bearing mutations in selected neuronal populations.