Ih Current Is Necessary to Maintain Normal Dopamine Fluctuations and Sleep Consolidation in Drosophila

HCN channels are becoming pharmacological targets mainly in cardiac diseases. But apart from their well-known role in heart pacemaking, these channels are widely expressed in the nervous system where they contribute to the neuron firing pattern. Consequently, abolishing Ih current might have detrimental consequences in a big repertoire of behavioral traits. Several studies in mammals have identified the Ih current as an important determinant of the firing activity of dopaminergic neurons, and recent evidences link alterations in this current to various dopamine-related disorders. We used the model organism Drosophila melanogaster to investigate how lack of Ih current affects dopamine levels and the behavioral consequences in the sleep∶activity pattern. Unlike mammals, in Drosophila there is only one gene encoding HCN channels. We generated a deficiency of the DmIh core gene region and measured, by HPLC, levels of dopamine. Our data demonstrate daily variations of dopamine in wild-type fly heads. Lack of Ih current dramatically alters dopamine pattern, but different mechanisms seem to operate during light and dark conditions. Behaviorally, DmIh mutant flies display alterations in the rest∶activity pattern, and altered circadian rhythms. Our data strongly suggest that Ih current is necessary to prevent dopamine overproduction at dark, while light input allows cycling of dopamine in an Ih current dependent manner. Moreover, lack of Ih current results in behavioral defects that are consistent with altered dopamine levels

The energy balance theory: an unsatisfactory model of body composition fluctuations

AbstractDifferential weight and fat losses under isocaloric diets of distinct macronutrient composition are well-documented findings in obesity research.1-6 Such data are considered a result of inadequate methodology as it disagree with the energy balance theory.7 A recent mathematical analysis of this paradigm has found, however, serious analytical contradictions in its foundations.8 As an alternative, a mass balance model was proposed to explain the aforesaid body composition alterations. Here, we expand on this observation by contrasting both models. We show that mass balance explains a wide range of fending experiments including those concurring with the energy balance principle. The latter, however, is less flexible and results in poor forecasts in settings consistent with mass balance. The energy balance theory is thus an unsatisfactory model of body composition changes. Consequently, by shifting to a mass balance paradigm of obesity a much deeper understanding of this disease may follow in the near future.</jats:p

The mass balance model perfectly fits both Hall <i>et al</i>. underfeeding data and Horton <i>et al</i>. overfeeding data

Abstract Background &amp; Aims Recently, the validity of mass balance model (MBM) was questioned based on two feeding studies. Thus, we simulated both of these feeding trials. Methods MBM describes the temporal evolution of body weight and body composition under a wide variety of feeding experiments. This computational study simulated, utilizing MBM, the underfeeding trial by Hall et al. (Cell Metab. 2015;22:427-36) and the overfeeding trial by Horton et al. (Am J Clin Nutr. 1995;62:19-29). Results Our simulation results indicate that data from both of these feeding trials perfectly match MBM-based predictions, i.e., MBM gives a remarkably accurate description of experimental data. Conclusions It is becoming increasingly clear that our model (MBM) is perfectly able to predict body weight and body composition fluctuations under a wide variety of feeding experiments. “There is a stupid humility that is not at all rare, and those afflicted with it are altogether unfit to become devotees of knowledge. As soon as a person of this type perceives something striking, he turns on his heel, as it were, and says to himself: “You have made a mistake. What is the matter with your senses? This cannot, may not, be the truth.” And then, instead of looking and listening again, more carefully, he runs away from the striking thing, as if he had been intimidated, and tries to remove it from his mind as fast as he can. For his inner canon says: “I do not want to see anything that contradicts the prevalent opinion. Am I called to discover new truths? There are too many old ones, as it is…” – Friedrich Nietzsche, The Gay Science (1882) </jats:sec