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Deciphering central role of VMH circuits in regulating energy balance

Periodic Reporting for period 1 - VMHCIRCUITS (Deciphering central role of VMH circuits in regulating energy balance)

Reporting period: 2015-04-01 to 2017-03-31

Appetite and feeding behavior is tightly regulated by brain circuits which closely monitor peripheral energy stores and initiate appropriate behavioral responses to procure food. While much have learned about the organization of the neuronal networks that regulate appetite, role of an important brain structure, ventromedial hypothalamus (VMH) in feeding behavior remained elusive. In this project we used state of the art neuronal circuit dissection tools to decipher functional role of VMH in food intake regulation.

Obesity remains a leading public health problem due to its association with cardiovascular disease, diabetes, cancer and other comorbidities. It is suggested that chronic imbalances in food intake and energy consumption contribute to excess weight gain. Therefore there is an urgent need to understand the basic brain organization that drives food intake and regulate energy homeostasis to uncover novel pharmacological targets for treatment of obesity and other feeding disorders. VMH region has long been implicated in energy homeostasis and appetite but some of the earlier observation had been controversial and direct evidence for the involvement of this region in feeding have been lacking. We aimed to decipher direct involvement of VMH in appetite regulation.

In this project, we aimed to elucidate role of VMH region in appetite regulation and body weight. Our goal was to use state of the art cell type specific neuronal activity manipulation tools to selectively engage VMH neurons and investigate the relationship between their activity and food intake. Our results concluded that VMH activity has a permissive role in suppressing appetite, i.e. inhibition of VMH neurons is necessary but not sufficient to engage food intake.
Work performed and Overview of the Results

In order to understand the role of VMH neurons in acute and chronic energy balance, we have performed a series of cell type specific neuronal activity manipulation e experiments while closely monitoring appetite and body weight phenotypes. To achieve this, we utilized state of the art chemogenetic actuators, DREADDs, to increase or decrease VMH neuronal activity.
Acute chemogenetic inhibition of VMH neurons: We have used a transgenic mouse line, sf1-cre, and a set of Cre-dependent viral tools, to selectively target chemogenetic activity manipulation tools to VMH neurons. Using stereotaxic delivery method, we expressed chemogenetic silencer DREADD, hM4D, in VMH-SF1 neurons. With the help of hM4D, we can acutely silence VMH neurons within minutes upon intraperitoneal injection its ligand, CNO. Our results suggest that acute chemogenetic silencing of VMH neurons does not increase food intake. This is in contrast to expectations from the literature that VMH lesions drive hyperphagia and obesity. We suggest that VMH lesions, which are chronic manipulations by nature, may have additional long lasting effects on appetite, which is not recapitulated in acute silencing experiments.

Chronic inhibition of VMH neurons: Classical lesion experiments have suffered from a setback of being nonspecific in the area of lesion as well as disruption of the fibers of passage through the periphery of VMH area. To resolve whether chronic loss of function of VMH neurons actually drive overeating, we used ablated VMH-SF1 neurons using virally targeted Cre-dependent caspase virus. Our cell type specific ablation experiment results confirmed that, as observed in classical lesioning studies, SF1 ablated animals are hyperphagic. Together with the acute chemogenetic silencing results, these experiments establish that reduced activity in SF1 neurons fails to drive veracious eating and appetite in short time scales but increases overall food intake in the longer terms.

Acute and chronic activation of VMH neurons: Silencing results established that VMH inhibition is not sufficient to drive acute food consumption. We next investigated whether VMH silencing is necessary for appetite. We used chemogenetic activator hM3D to selectively and acutely increase SF1 neuronal activity. Our results suggest that, both dark onset as well as food deprivation induced feeding can be strongly suppressed by increasing VMH-SF1 neuronal activity. Collectively these results suggest that VMH neuronal activity have permissive role in feeding in the short term but sufficient to cause positive energy balance in the longer terms.
Exploitation and dissemination of results: Our results implicate VMH as a novel target for appetite reduction. Understanding how SF1 activation suppresses food intake may provide novel targets for satiety circuits. To disseminate our findings, we are currently preparing our results as a manuscript for publication. In addition, these results will be orally presented in the international congress of Turkish Molecular Biology Organisation in September 2017.
Much of the current evidence about the role of VMH neurons in appetite regulation relies on lesion studies or genetic manipulations in VMH neurons. These studies, albeit have been very useful, lacks the temporal and cellular precision required to pinpoint whether VMH neurons are actually relevant for feeding and energy homeostasis. In this project, we applied state of the art circuit dissection tools to decipher contribution of VMH to feeding behavior. Our results have shown that VMH neuronal silencing is not sufficient but necessary for food intake. In the broader perspective, our work have added another satiety inducing brain region to the existing list and likely to lead additional work for exploitation of this pathway for novel obesity treatment options and thus relevant to broader public health.
Summary of results