Adipose tissue is commonly categorized into three types with distinct functions, phenotypes, and anatomical localizations. White adipose tissue (WAT) is the major energy store; the largest depots of WAT are found in subcutaneous or intravisceral sites. Brown adipose tissue (BAT) is responsible for energy dissipation during cold-exposure (i.e., non-shivering thermogenesis) and is primarily located in the interscapular region. Beige or brite (brown-in-white) adipose tissue can be found interspersed in WAT and can attain a brown-like phenotype. These three types of tissues also have endocrine functions and play major roles in whole body metabolism especially in obesity and its co-morbidities, such as cardiovascular disease. Over the last years, perivascular adipose tissue (PVAT) has emerged as an adipose organ with endocrine and paracrine functions. Pro and anti-inflammatory agents released by PVAT affect vascular health, and are implicated in the inflammatory aspects of atherosclerosis. PVAT shares several of the defining characteristics of brown adipose tissue, including its cellular morphology and expression of thermogenic genes characteristic for brown adipocytes. However, PVATs from different vessels are phenotypically different, and significant developmental differences exist between PVAT and other adipose tissues. Whether PVAT represents classical BAT, beige adipose tissue, or WAT with changing characteristics, is unclear. In this review, we summarize the current knowledge on how PVAT relates to other types of adipose tissue, both in terms of functionality, developmental origins, and its role in obesity-related cardiovascular disease and inflammation.

The rising prevalence of overweight and obesity across the globe is a major threat both to public health and economic development. This is mainly due to the link of obesity with the development and outcomes of non-communicable diseases (NCDs). NCDs are a leading cause of global death and disability, and reducing the burden of NCDs on patients and healthcare systems is of critical importance to improve public health. Obesity is projected to be the number one preventable risk factor for NCDs by 2035, and there is an urgent need to tackle the growing obesity rates in order to reduce NCD incidence and severity. Here, we review the current understanding of the impact of obesity on NCD burden in general, as well as the epidemiological and mechanistic relationship between obesity and some of the most common classes of NCDs. By literature review, we found that over 70% of NCDs have a documented association with obesity, highlighting the importance of a better understanding of the pathophysiologies underlying obesity/overweight as well as the interaction between obesity and NCDs in order to reduce global disease burden.

Brown adipose tissue (BAT) is a central thermogenic organ that enhances energy expenditure and cardiometabolic health. However, regulators that specifically increase the number of thermogenic adipocytes are still an unmet need. Here, we show that the cAMP-binding protein EPAC1 is a central regulator of adaptive BAT growth. In vivo, selective pharmacological activation of EPAC1 increases BAT mass and browning of white fat, leading to higher energy expenditure and reduced diet-induced obesity. Mechanistically, EPAC1 coordinates a network of regulators for proliferation specifically in thermogenic adipocytes, but not in white adipocytes. We pinpoint the effects of EPAC1 to PDGFRα-positive preadipocytes, and the loss of EPAC1 in these cells impedes BAT growth and worsens diet-induced obesity. Importantly, EPAC1 activation enhances the proliferation and differentiation of human brown adipocytes and human brown fat organoids. Notably, a coding variant ofRAPGEF3(encoding EPAC1) that is positively correlated with body mass index abolishes noradrenaline-induced proliferation of brown adipocytes. Thus, EPAC1 might be an attractive target to enhance thermogenic adipocyte number and energy expenditure to combat metabolic diseases.

The inherent complexity of brain tissue, with brain cells intertwining locally and projecting to distant regions, has made three-dimensional visualization of intact brains a highly desirable but challenging task in neuroscience. The natural opaqueness of tissue has traditionally limited researchers to techniques short of single cell resolution such as computer tomography or magnetic resonance imaging. By contrast, techniques with single-cell resolution required mechanical slicing into thin sections, which entails tissue distortions that severely hinder accurate reconstruction of large volumes. Recent developments in tissue clearing and light sheet microscopy have made it possible to investigate large volumes at micrometer resolution. The value of tissue clearing has been shown in a variety of tissue types and animal models. However, its potential for examining the songbird brain remains unexplored. Songbirds are an established model system for the study of vocal learning and sensorimotor control. They share with humans the capacity to adapt vocalizations based on auditory input. Song learning and production are controlled in songbirds by the song system, which forms a network of interconnected discrete brain nuclei. Here, we use the CUBIC and iDISCO+ protocols for clearing adult songbird brain tissue. Combined with light sheet imaging, we show the potential of tissue clearing for the investigation of connectivity between song nuclei, as well as for neuroanatomy and brain vasculature studies.

Regulated exocytosis is initiated by increased Ca ²⁺ concentrations in close spatial proximity to secretory granules, which is effectively prevented when the cell is at rest. Here we showed that exocytosis of zymogen granules in acinar cells was driven by Ca ²⁺ directly released from acidic Ca ²⁺ stores including secretory granules through NAADP-activated two-pore channels (TPCs). We identified OCaR1 (encoded by Tmem63a ) as an organellar Ca ²⁺ regulator protein integral to the membrane of secretory granules that controlled Ca ²⁺ release via inhibition of TPC1 and TPC2 currents. Deletion of OCaR1 led to extensive Ca ²⁺ release from NAADP-responsive granules under basal conditions as well as upon stimulation of GPCR receptors. Moreover, OCaR1 deletion exacerbated the disease phenotype in murine models of severe and chronic pancreatitis. Our findings showed OCaR1 as a gatekeeper of Ca ²⁺ release that endows NAADP-sensitive secretory granules with an autoregulatory mechanism preventing uncontrolled exocytosis and pancreatic tissue damage.

Recruitment of brown adipose tissue (BAT) is a potential new strategy for increasing energy expenditure (EE) to treat obesity. G protein-coupled receptors (GPCRs) represent promising targets to activate BAT, as they are the major regulators of BAT biological function. To identify new regulators of GPCR signaling in BAT, we studied the role of Regulator of G protein Signaling 2 (RGS2) in brown adipocytes and BAT. We combined pharmacological and genetic tools to investigate the role of RGS2 in BAT in vitro and in vivo. Adipocyte progenitors were isolated from wild-type (WT) and RGS2 knockout (RGS2-/-) BAT and differentiated to brown adipocytes. This approach was complemented with knockdown of RGS2 using lentiviral shRNAs (shRGS2). Adipogenesis was analyzed by Oil Red O staining and by determining the expression of adipogenic and thermogenic markers. Pharmacological modulators and fluorescence staining of F-acting stress fibers were employed to identify the underlying signaling pathways. In vivo, the activity of BAT was assessed by ex vivo lipolysis and by measuring whole-body EE by indirect calorimetry in metabolic cages. RGS2 is highly expressed in BAT, and treatment with cGMP-an important enhancer of brown adipocyte differentiation-further increased RGS2 expression. Loss of RGS2 strongly suppressed adipogenesis and the expression of thermogenic genes in brown adipocytes. Mechanistically, we found increased Gq/Rho/Rho kinase (ROCK) signaling in the absence of RGS2. Surprisingly, in vivo analysis revealed elevated BAT activity in RGS2-deficient mice that was caused by enhanced Gs/cAMP signaling. Overall, RGS2 regulates two major signaling pathways in BAT: Gq and Gs. On the one hand, RGS2 promotes brown adipogenesis by counteracting the inhibitory action of Gq/Rho/ROCK signaling. On the other hand, RGS2 decreases the activity of BAT through the inhibition of Gs signaling and cAMP production. Thus, RGS2 might represent a stress modulator that protects BAT from overstimulation.