Molecular Control of Metabolic Homeostasis

Our group is interested in the study of the mechanisms that regulate metabolic homeostasis, both at the peripheral level and in the central nervous system.

We initially discovered that the transcription factor Alx3 is expressed in pancreatic islets of Langerhans, where it participates in the transcriptional regulation of the insulin gene in beta cells. We subsequently documented that Alx3 deficiency compromises cell survival in pancreatic islets and impairs glycemic control. In glucagon-expressing alpha cells, we documented that Alx3 acts as a sensor of glucose levels through a mechanism that modulates Pax6 activity. We found that in response to fluctuations in blood glucose levels, Alx3 triggers adaptive responses to maintain metabolic homeostasis and prevent the effects of glucotoxicity, suggesting a possible contribution as an etiopathogenic factor in diabetes mellitus.

In the central nervous system, we have investigated the mechanisms by which diabetes affects the function of particularly vulnerable neurons in the brain, increasing the risk of neurodegeneration as indicated by numerous epidemiological studies. Focusing on Parkinson's disease, we have found that diabetes induces changes in dopaminergic neurons that result in altered neurotransmission in the striatal nucleus. These changes affect the levels of proteins that regulate dopamine release and reuptake. Furthermore, we demonstrated that dopaminergic neurons of diabetic mice are more sensitive to neuronal damage and therefore more vulnerable to neurodegeneration leading to motor impairment.

At the hypothalamic level, we determined that Alx3 is expressed in the arcuate nucleus and is involved in the regulation of food intake. Interestingly, Alx3-deficient mice eat less than controls, and our experiments indicate that, independently of its function in the pancreas, in the hypothalamus Alx3 participates in the maintenance of systemic metabolic homeostasis at least at three levels: 1, regulation of food intake; 2, regulation of metabolic partitioning that determines fat distribution and body mass; and 3, regulation of energy balance.

We have further addressed the study of the importance of circadian rhythms using a mouse model (Aphakia, spontaneous mutation in Pitx3) with a congenital eye defect. We determined that these mice lack innervation of the suprachiasmatic nucleus, the central circadian pacemaker, by retinal axons. As a consequence, locomotor activity, food intake, energy expenditure and hormone secretion oscillate independently and out-of-phase in each individual in relation to light and dark cycles. Using molecular-level determinations we found that molecular cloks both in both the central pacemaker  and  peripheral organs such as the liver and brown adipose tissue are dysfunctional. Surprisingly, we found that metabolic programming by restricting food to a certain time period synchronizes metabolic molecular clocks in the periphery but not the central pacemaker. Thus, our results indicate that early establishment of retinal contacts with the suprachiasmatic nucleus is important for the generation of metabolic oscillations induced by food intake cycles.

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