The Role of the Paraventricular Hypothalamus in the Rhythmic Regulation of Feeding and Metabolism
Obesity has reached epic proportions, in the US alone, over 70 million adults are obese. Despite the alarming
growth of this worldwide epidemic, the current therapeutics for obesity are limited in efficacy. For centuries,
overconsumption has been an evident culprit in obesity pathogenesis; however, the underlying cause of obesity
is a multifaceted biological problem, which has yet to be fully understood. Recent research has revealed that the
intrinsic biological clocks throughout the body are essential to the regulation of feeding and body weight
homeostasis. Large scale epidemiological studies on shift workers show that disruption of the natural circadian
patterns predisposes individuals to adiposity. Other research on rodent models of diet-induced obesity (DIO)
show an initial blunting of diurnal feeding and locomotor activity on high fat diet feeding, indicating a bidirectional
relationship between obesity and the circadian clock. Ultimately, both shift workers and DIO mice have
widespread desynchrony across peripheral tissues and the central clock. This decoupling suggests that body-
wide clock desynchrony may be involved in the pathogenesis of obesity. This proposal is centered on
understanding the circadian mechanisms that drive rhythmic energy intake and expenditure. More specifically,
the proposal focuses on the paraventricular nucleus (PVN) of the hypothalamus for its vital function as both
integrator and regulator of satiety and metabolism. Once thought to function merely as a peripheral clock to the
master clock (the suprachiasmatic nucleus [SCN]), the PVN has been identified to have its own intrinsic clock.
Electrophysiological recordings reveal diurnal fluctuations in the activity of inhibitory GABAergic neurons relaying
nutrient information to the PVN. These fluctuations appear to be driven by BMAL1 (Brain and Muscle ARNT-
Like1), an essential circadian transcription factor for maintaining robust rhythms in a variety of cells across the
body. Importantly, our preliminary data demonstrates that inducible loss of BMAL1 function in the PVN
corresponds to arrhythmic food intake in mice. This proposal will investigate the role of BMAL1 driven
mechanisms in the PVN as a central driver for governing patterns of energy balance. We will attempt to define
the respective roles of the PVN and SCN in mediating diurnal energy intake and metabolism. In addition, to
further characterize the interworking of the PVN rhythmicity, the proposal will also address which PVN neuronal
subtypes, such as corticotrophin releasing hormone (CRH)-expressing neurons, drive diurnal energy intake and
metabolism. At the molecular level, we will use high throughput genomic approaches to illuminate the molecular
machinery by which BMAL1 regulates the PVN's rhythmic functions. The successful completion of these aims
will establish for the first time a previously unknown role of the PVN as a rhythmic regulator of energy intake and
body weight homeostasis. In all, a complete understanding of the neural mechanisms governing consumption
and energy homeostasis is needed to develop pharmacological and behavioral therapeutics to effectively combat
obesity.
