The brain is fundamental in the regulation of appetite, body weight and metabolism. Specifically, there is a small group of hypothalamic neurons, called POMC, that detect and integrate the signals that inform about the energetic state of the organism and activate the appropriate physiological responses. These neurons are sensitive to the fluctuations of nutrients such as glucose, fatty acids and aminoacids. POMC neurons detect changes in nutrient availability, but the molecular mechanisms involved are not known in detail. Changes in the form of mitochondria, a phenomenon known as mitochondrial dynamics, are also a mechanism of energy adaptation in the change of metabolic conditions, to adapt the needs of the cells. Now, a research project co-chaired by Marc Claret, at the Biomedical Research Institute IDIBAPS and Antonio Zorzano, at the Barcelona Research Institute in Biomedicine, reveals the connection between the POMC neurons of the hypothalamus, the release of insulin from the pancreas and describe the molecular mechanisms behind it.
The researchers publish the study in the journal Cell Metabolism and the first authors are Sara Ramírez and Alicia G. Gómez-Valadés, both at IDIBAPS. To determine if the defects in the mitochondrial dynamics of this small nucleus of POMC neurons could cause alterations in metabolism, the researchers removed a mitochondrial protein, mitofusin 1, in these cells. First, the scientists observed that these mice altered the detection of glucose levels and adaptation between the fasting state and after being fed. Secondly, they found that these defects lead to glucose metabolism disorders caused by lower insulin secretion. It was surprising to find that these neurons are involved not only in nutrition control, which was already known, but also in controlling the amount of insulin secreted by pancreatic beta cells. Scientists have observed for the first time that this communication between the hypothalamus and the pancreas depends on the activity of the protein Mitofusin 1, and therefore on the energy of the mitochondria. Therefore they have studied to understand some molecular details of this connection.
They describe that the alterations are due to a disproportionate, though transitory, increase in the production of reactive oxygen species (free radicals, ROS) in the hypothalamus. When ROS levels in the hypothalamus are experimentally neutralized, the pancreas begins to secrete proper insulin levels again. Marc Claret, head of the Neuronal Metabolism Control Group at IDIBAPS, explains that the findings also suggest pathological implications of this animal model, since a high-fat diet makes these mice more susceptible to diabetes development. Mitochondrial dynamics is responsive to metabolic challenges and constitutes a central mechanism for bioenergetic adaptations to cell requirements. Study data show that fed state is associated with mitochondrial elongation in ARC POMC neurons and that MFN1 is required for appropriate mitochondrial shape adjustments and global hypothalamic transcriptional response during metabolic challenges. The team also demonstrated that loss of MFN1 in POMC neurons impairs central glucose sensing and insulin release, conferring higher susceptibility to develop diabetes in an obesogenic environment.
The involvement of the hypothalamus in insulin release control has been known for decades, albeit the identity of the neurons mediating such effects has remained elusive. Previous studies had hinted that POMC neurons could be implicated as central delivery of a-MSH or a melanocortin receptor agonist lowered serum insulin. However, more direct evidence was lacking. Thus, defective POMC neuronal function may be involved in the pathophysiology of altered insulin release in type 2 diabetes. Insulin segregation is an important phenomenon in relation to diabetes. Type 2 diabetic patients, who represent 90% of people with diabetes, have less beta cells and less ability to secrete insulin in response to glucose. If this phenomenon can be corrected not only by the pancreas, but also by the removal of cerebral oxidative stress, it would certainly allow better management of the disease. It is to be evaluated which molecule or antioxidant supplement can best perform this effect.
- edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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