cAMP driven UCP1 induction in human adipocytes requires ATGL-catalyzed lipolysis.

Objective: The uncoupling protein 1 (UCP1) is induced in brown or "beige" adipocytes through catecholamine-induced cAMP signaling, which activates diverse transcription factors. UCP1 expression can also be enhanced by PPARγ agonists such as rosiglitazone (Rsg). However, it is unclear whether this upregulation results from de-novo differentiation of beige adipocytes from progenitor cells, or from the induction of UCP1 in pre-existing adipocytes.

PPARγ activation by lipolysis-generated ligands is required for cAMP dependent induction in human thermogenic adipocytes.

Objective: The uncoupling protein 1 (UCP1) is induced in brown or "beige" adipocytes through catecholamine-induced cAMP signaling, which activates diverse transcription factors. UCP1 expression can also be enhanced by PPARγ agonists such as rosiglitazone (Rsg). However, it is unclear whether this upregulation results from de-novo differentiation of beige adipocytes from progenitor cells, or from the induction of UCP1 in pre-existing adipocytes.

Adipose tissue as a linchpin of organismal ageing.

Ageing is a conserved biological process, modulated by intrinsic and extrinsic factors, that leads to changes in life expectancy. In humans, ageing is characterized by greatly increased prevalence of cardiometabolic disease, type 2 diabetes and disorders associated with impaired immune surveillance. Adipose tissue displays species-conserved, temporal changes with ageing, including redistribution from peripheral to central depots, loss of thermogenic capacity and expansion within the bone marrow.

linc-ADAIN, a human adipose lincRNA, regulates adipogenesis by modulating KLF5 and IL-8 mRNA stability.

Adipose tissue remodeling and dysfunction, characterized by elevated inflammation and insulin resistance, play a central role in obesity-related development of type 2 diabetes (T2D) and cardiovascular diseases. Long intergenic non-coding RNAs (lincRNAs) are important regulators of cellular functions. Here, we describe the functions of linc-ADAIN (adipose anti-inflammatory), an adipose lincRNA that is downregulated in white adipose tissue of obese humans.

Regulation of lipolysis by 14-3-3 proteins on human adipocyte lipid droplets.

Adipocyte lipid droplets (LDs) play a crucial role in systemic lipid metabolism by storing and releasing lipids to meet the organism's energy needs. Hormonal signals such as catecholamines and insulin act on adipocyte LDs, and impaired responsiveness to these signals can lead to uncontrolled lipolysis, lipotoxicity, and metabolic disease. To investigate the mechanisms that control LD function in human adipocytes, we applied proximity labeling mediated by enhanced ascorbate peroxidase (APEX2) to identify the interactome of PLIN1 in adipocytes differentiated from human mesenchymal progenitor cells.

A distinct class of hematopoietic stem cells develop from the human yellow bone marrow.

Aging and metabolic diseases are accompanied by systemic inflammation, but the mechanisms that induce this state are not known. We developed a human bone-marrow organoid system to explore mechanisms underlying metabolic-disease associated systemic inflammation. We find that a distinct type of hematopoietic stem cell (HSC) develops in the adipose-rich, yellow bone marrow, which is known to gradually replace the hematopoietic red marrow as we age and during metabolic disease.

Wnt signaling preserves progenitor cell multipotency during adipose tissue development.

Mesenchymal stem/progenitor cells are essential for tissue development and repair throughout life, but how they are maintained under chronic differentiation pressure is not known. Using single-cell transcriptomics of human progenitor cells we find that adipose differentiation stimuli elicit two cellular trajectories: one toward mature adipocytes and another toward a pool of non-differentiated cells that maintain progenitor characteristics. These cells are induced by transient Wnt pathway activation and express numerous extracellular matrix genes and are therefore named structural Wnt-regulated adipose tissue cells.

A neurogenic signature involving monoamine Oxidase-A controls human thermogenic adipose tissue development.

Mechanisms that control 'beige/brite' thermogenic adipose tissue development may be harnessed to improve human metabolic health. To define these mechanisms, we developed a species-hybrid model in which human mesenchymal progenitor cells were used to develop white or thermogenic/beige adipose tissue in mice. The hybrid adipose tissue developed distinctive features of human adipose tissue, such as larger adipocyte size, despite its neurovascular architecture being entirely of murine origin.

Perinatal fat progenitors shape adult metabolism.

Adipose tissue plays a critical role in systemic metabolism. This work describes how perturbations in the adipocyte progenitor cell repertoire during the perinatal period exert long-lasting metabolic effects in adulthood.

Angiogenesis in adipose tissue and obesity.

While most tissues exhibit their greatest growth during development, adipose tissue is capable of additional massive expansion in adults. Adipose tissue expandability is advantageous when temporarily storing fuel for use during fasting, but becomes pathological upon continuous food intake, leading to obesity and its many comorbidities. The dense vasculature of adipose tissue provides necessary oxygen and nutrients, and supports delivery of fuel to and from adipocytes under fed or fasting conditions.

CRISPR-enhanced human adipocyte browning as cell therapy for metabolic disease.

Obesity and type 2 diabetes are associated with disturbances in insulin-regulated glucose and lipid fluxes and severe comorbidities including cardiovascular disease and steatohepatitis. Whole body metabolism is regulated by lipid-storing white adipocytes as well as "brown" and "brite/beige" adipocytes that express thermogenic uncoupling protein 1 (UCP1) and secrete factors favorable to metabolic health. Implantation of brown fat into obese mice improves glucose tolerance, but translation to humans has been stymied by low abundance of primary human beige adipocytes.

Adipocyte Heterogeneity Underlying Adipose Tissue Functions.

Adipose tissue distribution in the human body is highly heterogeneous, and the relative mass of different depots is differentially associated with metabolic disease risk. Distinct functions of adipose depots are mediated by their content of specialized adipocyte subtypes, best exemplified by thermogenic adipocytes found in specific depots. Single-cell transcriptome profiling has been used to define the cellular composition of many tissues and organs, but the large size, buoyancy, and fragility of adipocytes have rendered it challenging to apply these techniques to understand the full complexity of adipocyte subtypes in different depots.

Voices: Insulin and beyond.

Marking insulin's centennial, we share stories of researchers and clinicians whose seminal work has advanced our understanding of insulin, islet biology, insulin resistance, and diabetes. The past century of pursuing the "hormone of hormones" and advancing diabetes therapies is replete with stories of collaboration, perseverance, and triumph.

Cellular Heterogeneity in Adipose Tissues.

Adipose tissue depots in distinct anatomical locations mediate key aspects of metabolism, including energy storage, nutrient release, and thermogenesis. Although adipocytes make up more than 90% of adipose tissue volume, they represent less than 50% of its cellular content. Here, I review recent advances in genetic lineage tracing and transcriptomics that reveal the identities of the heterogeneous cell populations constituting mouse and human adipose tissues.

PAPPA-mediated adipose tissue remodeling mitigates insulin resistance and protects against gestational diabetes in mice and humans.

Pregnancy is a physiological state of continuous adaptation to changing maternal and fetal nutritional needs, including a reduction of maternal insulin sensitivity allowing for appropriately enhanced glucose availability to the fetus. However, excessive insulin resistance in conjunction with insufficient insulin secretion results in gestational diabetes mellitus (GDM), greatly increasing the risk for pregnancy complications and predisposing both mothers and offspring to future metabolic disease. Here, we report a signaling pathway connecting pregnancy-associated plasma protein A (PAPPA) with adipose tissue expansion in pregnancy.

Human thermogenic adipocyte regulation by the long noncoding RNA LINC00473.

Human thermogenic adipose tissue mitigates metabolic disease, raising much interest in understanding its development and function. Here, we show that human thermogenic adipocytes specifically express a primate-specific long non-coding RNA, which is highly correlated with UCP1 expression and decreased in obesity and type-2 diabetes. is detected in progenitor cells, and increases upon differentiation and in response to cAMP.

Diverse repertoire of human adipocyte subtypes develops from transcriptionally distinct mesenchymal progenitor cells.

Single-cell sequencing technologies have revealed an unexpectedly broad repertoire of cells required to mediate complex functions in multicellular organisms. Despite the multiple roles of adipose tissue in maintaining systemic metabolic homeostasis, adipocytes are thought to be largely homogenous with only 2 major subtypes recognized in humans so far. Here we report the existence and characteristics of 4 distinct human adipocyte subtypes, and of their respective mesenchymal progenitors.

Exercise Rescues Gene Pathways Involved in Vascular Expansion and Promotes Functional Angiogenesis in Subcutaneous White Adipose Tissue.

Exercise mitigates chronic diseases such as diabetes, cardiovascular diseases, and obesity; however, the molecular mechanisms governing protection from these diseases are not completely understood. Here we demonstrate that exercise rescues metabolically compromised high fat diet (HFD) fed mice, and reprograms subcutaneous white adipose tissue (scWAT). Using transcriptomic profiling, scWAT was analyzed for HFD gene expression changes that were rescued by exercise.

Generation of Functional Human Adipose Tissue in Mice from Primed Progenitor Cells.

This research describes the use of human mesenchymal progenitor cells for generating functional adipose tissue in a nude mouse model. Further preclinical development of the methods and insights described in this article can lead to therapeutic use of these cells in regenerative and reconstructive medicine.

Syndromic congenital myelofibrosis associated with a loss-of-function variant in .

There is a Commentary on this article in this issue.

Distinct adipocyte progenitor cells are associated with regional phenotypes of perivascular aortic fat in mice.

Objective: Perivascular adipose tissue depots around the aorta are regionally distinct and have specific functional properties. Thoracic aorta perivascular adipose tissue (tPVAT) expresses higher levels of thermogenic genes and lower levels of inflammatory genes than abdominal aorta perivascular adipose tissue (aPVAT). It is not known whether this distinction is due to the in-vivo functional environment or to cell-autonomous traits that persist outside the in-vivo setting.

Human White Adipocytes Convert Into "Rainbow" Adipocytes In Vitro.

White adipocytes are plastic cells able to reversibly transdifferentiate into brown adipocytes and into epithelial glandular cells under physiologic stimuli in vivo. These plastic properties could be used in future for regenerative medicine, but are incompletely explored in their details. Here, we focused on plastic properties of human mature adipocytes (MA) combining gene expression profile through microarray analysis with morphologic data obtained by electron and time lapse microscopy.

Visualization of self-delivering hydrophobically modified siRNA cellular internalization.

siRNAs are a new class of therapeutic modalities with promising clinical efficacy that requires modification or formulation for delivery to the tissue and cell of interest. Conjugation of siRNAs to lipophilic groups supports efficient cellular uptake by a mechanism that is not well characterized. Here we study the mechanism of internalization of asymmetric, chemically stabilized, cholesterol-modified siRNAs (sd-rxRNAs) that efficiently enter cells and tissues without the need for formulation.

Human 'brite/beige' adipocytes develop from capillary networks, and their implantation improves metabolic homeostasis in mice.

Uncoupling protein 1 (UCP1) is highly expressed in brown adipose tissue, where it generates heat by uncoupling electron transport from ATP production. UCP1 is also found outside classical brown adipose tissue depots, in adipocytes that are termed 'brite' (brown-in-white) or 'beige'. In humans, the presence of brite or beige (brite/beige) adipocytes is correlated with a lean, metabolically healthy phenotype, but whether a causal relationship exists is not clear.

Human adipose tissue expansion in pregnancy is impaired in gestational diabetes mellitus.

Aims/hypothesis: During pregnancy, adipose tissue (AT) must expand to support the growing fetus and the future nutritional needs of the offspring. Limited expandability of AT is associated with insulin resistance, attributed to ectopic lipid deposition. This study aimed to investigate human AT expandability during pregnancy and its role in the pathogenesis of gestational diabetes mellitus (GDM).