There is only one known portal system in the mammalian brain - that of the pituitary gland, first identified in 1933 by Popa and Fielding. Here we describe a second portal pathway in the mouse linking the capillary vessels of the brain’s clock suprachiasmatic nucleus (SCN) to those of the organum vasculosum of the lamina terminalis (OVLT), a circumventricular organ. The localized blood vessels of portal pathways enable small amounts of important secretions to reach their specialized targets in high concentrations without dilution in the general circulatory system. These brain clock portal vessels point to an entirely new route and targets for secreted SCN signals, and potentially restructures our understanding of brain communication pathways.

Introduction 635 Discussion 1070 Acknowledgments: Imaging was performed with support from the the Barnard College Imaging Facility and the National Science Foundation (NSF 1828264).

Systemic glucose metabolism and insulin activity oscillate in response to diurnal rhythms and nutrient availability with the necessary involvement of adipose tissue to maintain metabolic homeostasis. However, the adipose‐intrinsic regulatory mechanism remains elusive. Here, the dynamics of PPARγ acetylation in adipose tissue are shown to orchestrate metabolic oscillation in daily rhythms. Acetylation of PPARγ displays a diurnal rhythm in young healthy mice, with the peak at zeitgeber time 0 (ZT0) and the trough at ZT18. This rhythmic pattern is deranged in pathological conditions such as obesity, aging, and circadian disruption. The adipocyte‐specific acetylation‐mimetic mutation of PPARγ K293Q (aKQ) restrains adipose plasticity during calorie restriction and diet‐induced obesity, associated with proteolysis of a core circadian component BMAL1. Consistently, the rhythmicity in glucose tolerance and insulin sensitivity is altered in aKQ and the complementary PPARγ deacetylation‐mimetic K268R/K293R (2KR) mouse models. Furthermore, the PPARγ acetylation‐sensitive downstream target adipsin is revealed as a novel diurnal factor that destabilizes BMAL1 and mediates metabolic rhythms. These findings collectively signify that PPARγ acetylation is a hinge connecting adipose plasticity and metabolic rhythms, the two determinants of metabolic health.

Biological neural networks operate at several levels of granularity, from the individual neuron to local neural circuits to networks of thousands of cells. The daily oscillation of the brain's master clock in the suprachiasmatic nucleus (SCN) rests on a yet to be identified network of connectivity among its ~20,000 neurons. The SCN provides an accessible model to explore neural organization at several levels of organization. To relate cellular to local and global network behaviors, we explore network topology by examining SCN slices in three orientations using immunochemistry, light and confocal microscopy, real-time imaging, and mathematical modeling. Importantly, the results reveal small local groupings of neurons that form intermediate structures, here termed "phaseoids" which can be identified through stable local phase differences of varying magnitude among neighboring cells. These local differences in phase are distinct from the global phase relationshipthat between individual cells and the mean oscillation of the overall SCN. The magnitude of the phaseoids' local phase differences are associated with a global phase gradient observed in the SCN's rostral-caudal extent. Modeling results show that a gradient in connectivity strength can explain the observed gradient of phaseoid strength, an extremely parsimonious explanation for the heterogeneous oscillatory structure of the SCN. Significance statementOscillation is a fundamental property of information sensing and encoding in the brain. Using real time imaging and modeling, we explore encoding of time by examining circadian oscillation in single neurons, small groups of neurons, and the entire nucleus, in the brain's master: the suprachiasmatic nucleus. New insights into the network organization underlying circadian rhythmicity include the discovery of intermediate structures, termed 'phaseoids', characterized by groups of neurons which are stably out of phase with their neighbors. Modeling indicates that the pattern of phaseoids across the tissue encompasses a gradient in connectivity strength from the rostral to caudal aspects of the nucleus. Anisotropy in network organization emerges from comparisons of phaseoids and connectivity gradients in sagittal, horizontal and coronal slices.