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Adipocyte dysfunction plays a critical role in the pathogenesis of metabolic diseases, including type 2 diabetes (T2D). Human induced pluripotent stem cells (hiPSCs) offer a powerful platform for generating white, beige, and brown adipocytes, supporting both disease modeling and therapeutic research. This review provides a comprehensive summary of current differentiation methods to produce three functionally mature adipocyte types from pluripotent stem cells (PSCs), including forced gene expression techniques, developmental biology-inspired approaches, and advanced three-dimensional (3D) culture systems that enhance cellular maturity and functional relevance. PSC-derived white adipocytes contribute to modeling adipocyte dysfunction not only in conditions such as insulin resistance, lipodystrophy, and premature aging but also in more complex metabolic diseases, including T2D, facilitating the investigation of disease mechanisms and the identification of novel therapeutic targets. In addition, iPSC-based models provide a robust platform for exploring genetic regulation by genome-wide association studies (GWAS)–identified variants through population genetics. This review also evaluates the therapeutic potential of iPSC-derived white, beige, and brown adipocytes in cell transplantation therapy for metabolic diseases, with a focus on engraftment potential and metabolic improvement. Enhancing the maturity and subtype specificity of PSC-derived adipocytes is expected to accelerate the development of personalized medicine and innovative therapeutic strategies for metabolic diseases. Graphical Abstract

Background Studies comparing fat graft–processing methods are limited. Objectives The aim of the authors of this study was to evaluate in vitro properties and tissue quality of fat grafts obtained with REVOLVE (filtration-based system [FBS], Allergan Aesthetics, an AbbVie Company, Branchburg, NJ), LipoGrafter (decantation-based system [DBS], MTF Biologics, Edison, NJ), or standard decantation (SD). Methods Lipoaspirate was processed from 6 patients using either FBS, DBS, or SD. For each graft, the volume composition (free oil, fat, aqueous fluid, and cellular debris), hematocrit content, adipocyte activity and count, and fat particle size were analyzed. The progenitor cell count (CD45−/CD31−/CD34+ cells analyzed by fluorescence-activated cell sorting) and colony-forming units (CFUs) of the stromal vascular fraction (SVF) were assessed. Results Mean (±standard error of the mean) fat content was highest for FBS grafts at 77.7% ± 3.6%, followed by DBS grafts at 71.2% ± 4.1% and SD grafts at 60.8% ± 3.8% (P < .01, FBS vs SD). Free oil contaminants were significantly lower for FBS compared with DBS and SD grafts (0% ± 0.4% vs 6.2% ± 2.0% and 15.6% ± 4.0%, respectively; P < .05 for all comparisons). Hematocrit levels were numerically lower for FBS compared with DBS and SD grafts (optical density: 0.5 ± 0.1 vs 4.5 ± 6.3 and 5.5 ± 6.7, respectively). The size of mean fat particles was highest for FBS compared with DBS and SD grafts (1418.9 ± 30.5 vs 989.3 ± 51.1 and 1172.0 ± 76.2 µm, respectively; P < .05 for all comparisons). FBS contained more adipocytes and greater adipocyte activity vs DBS and SD grafts. SVF obtained from FBS grafts had more progenitors and comparable CFUs vs DBS and SD grafts. Conclusions Lipoaspirate processed with FBS produced the highest quality fat grafts vs DBS and SD in this in vitro study. Level of Evidence: 5 (Therapeutic)

Adipose tissue plays an essential role in systemic metabolism with white adipose tissue (WAT) making up most of the tissue and being involved in the regulation of energy homeostasis, and brown and beige adipose tissue (BAT) exhibiting thermogenic activity. There is promise in the conversion of white adipocytes into beige ones as a therapeutic potential to control and enhance systemic metabolism, but it is difficult to maintain this transformation in vivo because we do not fully understand the mechanism of conversion. In this study, we applied atomic force microscopy (AFM) to characterize beige or white adipocytes during the process of differentiation for morphology, roughness, adhesion, and elasticity at different time points. As cells differentiated to white and beige adipocytes, they exhibited morphological changes as they lipid loaded, transitioning from flattened elongated cells to a rounded shape indicating adipogenesis. While there was an initial decrease in elasticity for both beige and white adipocytes, white adipocytes exhibited a higher elasticity than beige adipocytes at all time points. Beige and white adipogenesis exhibited a decrease in adhesion energy compared to preadipocytes, yet at day 12, white adipocytes had a significant increase in adhesion energy compared to beige adipocytes. This work shows significant differences in the mechanical properties of white vs. beige adipocytes during differentiation. Results from this study contribute to a better understanding of the differentiation of adipocytes which are vital to the therapeutic induction, engineered models, and maintenance of beige adipocytes as a potential approach for enhancing systemic metabolism.

[This corrects the article DOI: 10.1371/journal.pone.0173713.].

Expression of bone morphogenetic protein 4 (BMP4) in adipocytes of white adipose tissue (WAT) produces “white adipocytes” with characteristics of brown fat and leads to a reduction of adiposity and its metabolic complications. Although BMP4 is known to induce commitment of pluripotent stem cells to the adipocyte lineage by producing cells that possess the characteristics of preadipocytes, its effects on the mature white adipocyte phenotype and function were unknown. Forced expression of a BMP4 transgene in white adipocytes of mice gives rise to reduced WAT mass and white adipocyte size along with an increased number of a white adipocyte cell types with brown adipocyte characteristics comparable to those of beige or brite adipocytes. These changes correlate closely with increased energy expenditure, improved insulin sensitivity, and protection against diet-induced obesity and diabetes. Conversely, BMP4-deficient mice exhibit enlarged white adipocyte morphology and impaired insulin sensitivity. We identify peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC1α) as the target of BMP signaling required for these brown fat-like changes in WAT. This effect of BMP4 on WAT appears to extend to human adipose tissue, because the level of expression of BMP4 in WAT correlates inversely with body mass index. These findings provide a genetic and metabolic basis for BMP4’s role in altering insulin sensitivity by affecting WAT development.

Adipose tissue, a central player in energy balance, exhibits significant metabolic flexibility that is often compromised in obesity and type 2 diabetes (T2D). Mitochondrial dysfunction within adipocytes leads to inefficient lipid handling and increased oxidative stress, which together promote systemic metabolic disruptions central to obesity and its complications. This review explores the pivotal role that mitochondria play in altering the metabolic functions of the primary adipocyte types, white, brown, and beige, within the context of obesity and T2D. Specifically, in white adipocytes, these dysfunctions contribute to impaired lipid processing and an increased burden of oxidative stress, worsening metabolic disturbances. Conversely, compromised mitochondrial function undermines their thermogenic capabilities, reducing the capacity for optimal energy expenditure in brown adipocytes. Beige adipocytes uniquely combine the functional properties of white and brown adipocytes, maintaining morphological similarities to white adipocytes while possessing the capability to transform into mitochondria-rich, energy-burning cells under appropriate stimuli. Each type of adipocyte displays unique metabolic characteristics, governed by the mitochondrial dynamics specific to each cell type. These distinct mitochondrial metabolic phenotypes are regulated by specialized networks comprising transcription factors, co-activators, and enzymes, which together ensure the precise control of cellular energy processes. Strong evidence has shown impaired adipocyte mitochondrial metabolism and faulty upstream regulators in a causal relationship with obesity-induced T2D. Targeted interventions aimed at improving mitochondrial function in adipocytes offer a promising therapeutic avenue for enhancing systemic macronutrient oxidation, thereby potentially mitigating obesity. Advances in understanding mitochondrial function within adipocytes underscore a pivotal shift in approach to combating obesity and associated comorbidities. Reigniting the burning of calories in adipose tissues, and other important metabolic organs such as the muscle and liver, is crucial given the extensive role of adipose tissue in energy storage and release.

Obesity is a leading health problem facing the modern world; however, no effective therapy for this health issue has yet been developed. A promising research direction to identify novel therapies to prevent obesity has emerged from discoveries on development and function of brown/brite adipocytes in mammals. Importantly, there is evidence for the presence and function of active thermogenic brown adipocytes in both infants and adult humans. Several new investigations have shown that thermogenic adipocytes are beneficial to maintain glucose homeostasis, insulin sensitivity, and a healthy body fat content. Such thermogenic adipocytes have been considered as targets to develop a therapy for preventing obesity. This short review seeks to highlight recent findings on the development and function of brown/brite adipocytes in humans and to discuss potential treatments based on these adipocytes to reduce obesity and its related disorders.

Obesity, a major risk factor for various metabolic diseases, often results in dysfunctional white adipose tissue and altered adipogenesis leading to ectopic fat accumulation, inflammation, and insulin resistance. On the other hand, cashew ( Anacardium occidentale L.) nut worldwide consumption and production is increasing steadily, which augments the mass of byproducts to be discarded. Indeed, cashew apples and cashew shells have shown potent effects to lower adiposity weight in human and animal models. However, the direct effect on adipocyte differentiation still remains unexplored. Therefore, this study aimed to investigate the biological effect of cashew nut or kernel (CK), dried cashew apple (DA), and cashew shell (SH) ethanolic extracts on 3T3-L1 adipocyte differentiation and lipid accumulation. SH showed strong inhibition on adipocyte differentiation by downregulating transcription factors, PPARγ, C/EBPα, and SREBP-1. DA also inhibited the transcription factors accompanied by reduced lipid accumulation, while proteins for de novo lipogenesis were unchanged. Finally, CK did not alter any markers in adipocyte differentiation, however, interestingly adiponectin level was significantly increased. Concisely, our findings showed that CK ameliorates adiponectin production without interfering adipogenesis, while DA lowers lipid accumulation and SH suppresses adipogenesis.

Breast cancer progression is highly dependent on the heterotypic interaction between tumor cells and stromal cells of the tumor microenvironment. Cancer-associated adipocytes (CAAs) are emerging as breast cancer cell partners favoring proliferation, invasion, and metastasis. This article discussed the intersection between extracellular signals and the transcriptional cascade that regulates adipocyte differentiation in order to appreciate the molecular pathways that have been described to drive adipocyte dedifferentiation. Moreover, recent studies on the mechanisms through which CAAs affect the progression of breast cancer were reviewed, including adipokine regulation, metabolic reprogramming, extracellular matrix remodeling, and immune cell modulation. An in-depth understanding of the complex vicious cycle between CAAs and breast cancer cells is crucial for designing novel strategies for new therapeutic interventions.

Brown and beige adipocytes harbor the thermogenic capacity to adapt to environmental thermal or nutritional changes. Histone methylation is an essential epigenetic modification involved in the modulation of nonshivering thermogenesis in adipocytes. Here, we describe a molecular network leading by KMT5c, a H4K20 methyltransferase, that regulates adipocyte thermogenesis and systemic energy expenditure. The expression of Kmt5c is dramatically induced by a β3-adrenergic signaling cascade in both brown and beige fat cells. Depleting Kmt5c in adipocytes in vivo leads to a decreased expression of thermogenic genes in both brown and subcutaneous (s.c.) fat tissues. These mice are prone to high-fat-diet-induced obesity and develop glucose intolerance. Enhanced transformation related protein 53 (Trp53) expression in Kmt5c knockout (KO) mice, that is due to the decreased repressive mark H4K20me3 on its proximal promoter, is responsible for the metabolic phenotypes. Together, these findings reveal the physiological role for KMT5c-mediated H4K20 methylation in the maintenance and activation of the thermogenic program in adipocytes.