Adipose tissue demonstrates considerable plasticity and heterogeneity, enabling metabolic, cellular and structural adaptations to environmental signals. This adaptability is key for maintaining metabolic homeostasis. Impaired adipose tissue plasticity can lead to abnormal adipose tissue responses to metabolic cues, which contributes to the development of cardiometabolic diseases. In chronic obesity, white adipose tissue undergoes pathological remodelling marked by adipocyte hypertrophy, chronic inflammation and fibrosis, which are linked to local and systemic insulin resistance. Research data suggest that the capacity for healthy or unhealthy white adipose tissue remodelling might depend on the intrinsic diversity of adipose progenitor cells (APCs), which sense and respond to metabolic cues. This Review highlights studies on APCs as key determinants of adipose tissue plasticity, discussing differences between subcutaneous and visceral adipose tissue depots during development, growth and obesity. Modulating APC functions could improve strategies for treating adipose tissue dysfunction and metabolic diseases in obesity.

In obesity, adipose tissue (AT) expansion is accompanied by chronic inflammation. Altered lipid composition in the visceral or gonadal white AT (GWAT) directly drive AT macrophage (ATM) accumulation and activation to a proinflammatory phenotype. Sex steroid hormones modulate visceral vs subcutaneous lipid accumulation that correlates with metabolic syndrome, especially in men and post-menopausal women who are more prone to abdominal obesity. Prior studies demonstrated sex differences in GWAT lipid species in HFD-fed mice, but the role of sex hormones is still unclear. We hypothesized that sex hormone alterations with gonadectomy (GX) would further impact lipid composition in the obese GWAT. Untargeted lipidomics of obese GWAT identified sex differences in phospholipids, sphingolipids, sterols, fatty acyls, saccharo-lipids and prenol-lipids. Males had significantly more precursor fatty acids (palmitic, oleic, linoleic and arachidonic acid) than females and GX mice. Targeted lipidomics for fatty acids and oxylipins in the HFD-fed male and female GWAT stromal vascular fraction (SVF) identified higher omega-6 to omega-3 free fatty acid profile in males and differences in polyunsaturated fatty acids (PUFAs)-derived prostaglandins, thromboxanes and leukotrienes. Both obese male and female GWAT SVF showed increased levels of arachidonic acid (AA) derived oxylipins compared to their lean counterparts. Bulk RNA sequencing of sorted GWAT ATMs highlighted sex and diet differences in PUFA and oxylipin metabolism genes. These findings of sexual dimorphism in both stored lipid species and PUFA derived mediators with diet and GX emphasize sex-differences in lipid metabolism pathways that drive inflammation responses and metabolic disease risk in obesity.

Dietary fat composition has changed substantially during the obesity epidemic. As adipocyte hyperplasia is a major mechanism of adipose expansion, we aim to ascertain how dietary fats affect adipogenesis during obesity. We employ an unbiased dietary screen to identify oleic acid (OA) as the only dietary fatty acid that induces obesogenic hyperplasia at physiologic levels and show that plasma monounsaturated fatty acids (MUFAs), which are mostly OA, are associated with human obesity. OA stimulates adipogenesis in mouse and human adipocyte precursor cells (APCs) by increasing AKT2 signaling, a hallmark of obesogenic hyperplasia, and reducing LXR activity. High OA consumption decreases LXRα Ser196 phosphorylation in APCs, while blocking LXRα phosphorylation results in APC hyperproliferation. As OA is increasingly being incorporated into dietary fats due to purported health benefits, our finding that OA is a unique physiologic regulator of adipose biology underscores the importance of understanding how high OA consumption affects metabolic health.

Bone resorption by osteoclasts is a critical step in bone remodeling, a process important for maintaining bone homeostasis and repairing injured bone. We previously identified a bone marrow mesenchymal subpopulation, marrow adipogenic lineage precursors (MALPs), and showed that its production of RANKL stimulates bone resorption in young mice using Adipoq-Cre. To exclude developmental defects and to investigate the role of MALPs-derived RANKL in adult bone, we generated inducible reporter mice (Adipoq-CreER Tomato) and RANKL deficient mice (Adipoq-CreER RANKLflox/flox, iCKO). Single cell-RNA sequencing data analysis and lineage tracing revealed that Adipoq+ cells contain not only MALPs but also some mesenchymal progenitors capable of osteogenic differentiation. In situ hybridization showed that RANKL mRNA is only detected in MALPs, but not in osteogenic cells. RANKL deficiency in MALPs induced at 3 months of age rapidly increased trabecular bone mass in long bones as well as vertebrae due to diminished bone resorption but had no effect on the cortical bone. Ovariectomy (OVX) induced trabecular bone loss at both sites. RANKL depletion either before OVX or at 6 weeks post OVX protected and restored trabecular bone mass. Furthermore, bone healing after drill-hole injury was delayed in iCKO mice. Together, our findings demonstrate that MALPs play a dominant role in controlling trabecular bone resorption and that RANKL from MALPs is essential for trabecular bone turnover in adult bone homeostasis, postmenopausal bone loss, and injury repair.

Adipose tissue expands through hyperplasia and hypertrophy to store excess lipids, a process that is essential for the maintenance of metabolic homeostasis. The mechanisms regulating adipocyte recruitment from progenitors remain unclear. We have previously identified V-set and transmembrane domain-containing protein 2A (VSTM2A) as a factor promoting fat cell development in vitro. Whether VSTM2A impacts adipose tissue and systemic metabolism in vivo is still unknown.

We generated VSTM2A knockout mice (Vstm2a-/-) using clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) and fed them either a chow or high-fat diet. These mice were evaluated for body weight, adiposity, blood parameters, and glucose homeostasis.

Vstm2a-/- mice were viable and showed no body weight differences. Although adipose mass was similar, Vstm2a-/- mice had larger adipocytes, an effect linked to inflammation, ectopic lipid deposition, and impaired glucose and lipid metabolism. Transcriptomic analysis revealed that VSTM2A loss affects the expression of several genes in adipose tissue, including some related to the lysosome. Interestingly, acute lysosomal inhibition early in life is sufficient to cause adipocyte hypertrophy in adults.

VSTM2A is dispensable for adipose tissue formation, but its loss causes adipocyte hypertrophy and impairs glucose and lipid homeostasis. Our study also underscores a critical role of the lysosome in initiating adipogenesis.

A comparative transcriptomic analysis in adipose stem and progenitor cells (ASPCs) between obese and lean mice might facilitate the identification of novel adipogenic genes. Here, we compare transcriptomic differences in the ASPCs of subcutaneous adipose tissue (SAT) between the mice fed on a high-fat-diet (HFD) and the chow diet (CD)-fed mice by analyzing three independent single-cell RNA sequencing datasets. Six differential genes, including three up-regulated genes Aspn, Rrbp1, Fbln2 and three down-regulated genes Htra1, Plpp3, Efemp1, are identified and confirmed in HFD-fed mice. Further, the expression of these genes is found to be significantly diminished in the differentiated 3T3-L1 cells. Treatment with luteolin, a dietary flavonoid known to inhibit 3T3-L1 adipogenesis, reverses the decreased expression of Aspn, Htra1 and Efemp1. Furthermore, knockdown of Aspn, Htra1 and Efemp1 significantly facilitates 3T3-L1 adipogenesis. Together, these genes not only are differential in ASPCs between obese and lean mice, but also are the adipogenic inhibitory genes that can be up-regulated by luteolin treatment.

The transition from metabolically healthy obesity to the development of obesity-associated metabolic syndrome and cardiovascular disease is thought to be triggered by a loss in the functional integrity of adipose tissue. Although mature adipocytes are the primary functional units that carry out lipid partitioning in adipose tissue for the promotion of whole-body energy balance, they are supported by a heterogenous collection of nonadipocytes in the stroma. Research over the past couple of decades has expanded perspectives on the homeostatic and pathological roles of the nonadipocyte compartment. Adipose progenitors originate in the embryonic period and drive the developmental adipogenesis that establishes the set point of adiposity. A population of adipocyte progenitors reside in adult depots and serve an important homeostatic role as a reservoir to support adipocyte turnover. Adipocyte hypertrophy in obesity increases the rate of adipocyte death and the ability of progenitors to support this high rate of adipocyte turnover is important for the preservation of the lipid-buffering function of adipose tissue. Some evidence exists to suggest that impaired adipogenesis or a decline in progenitors capable of differentiation is a key event in the development of adipose dysfunction. The efficiency of macrophages to clear the debris and toxic lipids released from dead adipocytes lies at the fulcrum between preservation of adipose function and the progression toward chronic inflammation. Although macrophages in collaboration with other immune cells propagate the inflammation that underlies adipose dysfunction, there is now a greater appreciation for the diverse and unique roles of immune cells within adipose tissue.

Cellular turnover is fundamental for tissue homeostasis and integrity. Adipocyte turnover, accounting for 4% of the total cellular mass turnover in humans, is essential for adipose tissue homeostasis during metabolic stress. In obesity, an altered adipose tissue microenvironment promotes adipocyte death. To clear dead adipocytes, macrophages are recruited and form a distinctive structure known as crown-like structure; subsequently, new adipocytes are generated from adipose stem and progenitor cells in the adipogenic niche to replace dead adipocytes. Accumulating evidence indicates that adipocyte death, clearance, and adipogenesis are sophisticatedly orchestrated during adipocyte turnover. In this Review, we summarize our current understandings of each step in adipocyte turnover, discussing its key players and regulatory mechanisms.

Angiopoietin-like protein 8 (Angptl8), expressed in the liver and adipocytes, forms a complex with Angptl3 or Angptl4, which regulates lipoprotein lipase and triglyceride metabolism. However, the precise functions of adipocyte Angptl8 remain elusive. Here we report that adipocyte-specific inducible Angptl8-knockout (AT-A8-KO) male mice on normal diet showed minor phenotypic changes, but after a high-fat high fructose (HFHF) diet, exhibited decreased body weight gain and glycemia, elevated rectal temperature and early dark phase energy expenditure compared to the Cre controls. AT-A8-KO mice also displayed improved glucose tolerance, a trend for better insulin sensitivity, improved insulin-stimulated glucose uptake in adipose tissues, and reduced visceral adipose tissue crown-like structures, plasma MCP-1 and leptin levels. The results indicate the importance of adipose Angptl8 in the context of nutri-stress and obesity, as its deletion in mice promotes a metabolically healthy obese phenotype by slightly ameliorating obesity, improving glucose and energy homeostasis, and mitigating inflammation.

The promising results obtained in the PARADIGM-HF trial prompted the approval of sacubitril/valsartan (SAC/VAL) as a first-in-class treatment for heart failure with reduced ejection fraction (HFrEF) patients. The effect of SAC/VAL treatment was also studied in patients with heart failure with preserved ejection fraction (HFpEF) and, although improvements in New York Heart Association (NYHA) class, HF hospitalizations, and cardiovascular deaths were observed, these results were not so promising. However, the demand for HFpEF therapies led to the approval of SAC/VAL as an alternative treatment, although further studies are needed. We aimed to elucidate the effects of a 9-week SAC/VAL treatment in cardiac function and metabolism using a preclinical model of HFpEF, the Zucker Fatty and Spontaneously Hypertensive (ZSF1) rats. We found that SAC/VAL significantly improved diastolic function parameters and modulated respiratory quotient during exercise. Ex-vivo studies showed that SAC/VAL treatment significantly decreased heart, liver, spleen, and visceral fat weights; cardiac hypertrophy and percentage of fibrosis; lipid infiltration in liver and circulating levels of cholesterol and sodium. Moreover, SAC/VAL reduced glycerophospholipids, cholesterol, and cholesteryl esters while increasing triglyceride levels in cardiac tissue. In conclusion, SAC/VAL treatment improved diastolic and hepatic function, respiratory metabolism, reduced hypercholesterolemia and cardiac fibrosis and hypertrophy, and was able to modulate cardiac metabolic profile. Our findings might provide further insight into the therapeutic benefits of SAC/VAL treatment in obese patients with HFpEF.

The intricate regulatory mechanisms governing adipocyte differentiation are pivotal in elucidating the complex pathophysiology underlying obesity. This study aims to explore the dynamic changes in gene expression during the differentiation of 3T3-L1 adipocytes using transcriptomics methods. Protopanaxatriol (PPT) significantly inhibited adipocyte differentiation. To uncover the molecular mechanisms, we conducted an extensive transcriptomic analysis of adipocytes throughout various differentiation stages, comparing gene expression profiles before and after PPT treatment. The construction of 16 co-expression modules was achieved using weighted gene co-expression network analysis (WGCNA). The 838 differentially expressed genes in the blue module were highly correlated with PPT treatment. Further analysis revealed that PIKfyve, STAT3, JAK1, CTTN, TYK2, JAK3, STAT2, STAT5b, SOCS3, and IRF9 were core genes closely associated with adipocyte differentiation. This discovery underscores the potential pivotal function of these ten genes in regulating adipocyte differentiation. This study elucidated that PPT, an active ingredient in ginseng, could reduce lipid accumulation by inhibiting the differentiation of adipocyte precursors through the negative regulation of genes such as PIKfyve, STAT3, and JAK1. Finally, molecular docking identified potential binding sites for PPT on PIKfyve and JAK1. This study provides potential drug targets for preventing obesity and related metabolic diseases.

Visceral adipose tissue, a type of abdominal adipose tissue, is highly involved in lipolysis. Because increased visceral adiposity is strongly associated with the metabolic complications related with obesity, such as type 2 diabetes and cardiovascular disease, there is a need for precise, targeted, personalized and site-specific measures clinically. Existing studies showed that ectopic fat accumulation may be characterized differently among different populations due to complex genetic architecture and non-genetic or epigenetic components, ie, Asians have more and Africans have less visceral fat vs Europeans. In this review, we summarize the effects of multiple non-genetic and genetic factors on visceral fat distribution across races. Non-genetic factors include diet, socioeconomic status, sex hormones and psychological factors, etc. We examine genetic factors of racial differences in visceral fat content as well as possible regulatory pathways associated with interracial visceral fat distribution. A comprehensive understanding of both genetic and non-genetic factors that influence the distribution of visceral fat among races, leads us to predict risk of abdominal obesity and metabolic diseases in ethnic groups that enables targeted interventions through accurate diagnosis and treatment as well as reduced risk of obesity-associated complications.

Postprandial IL-1β surges are predominant in the white adipose tissue (WAT), but its consequences are unknown. Here, we investigate the role of IL-1β in WAT energy storage and show that adipocyte-specific deletion of IL-1 receptor 1 (IL1R1) has no metabolic consequences, whereas ubiquitous lack of IL1R1 reduces body weight, WAT mass, and adipocyte formation in mice. Among all major WAT-resident cell types, progenitors express the highest IL1R1 levels. In vitro, IL-1β potently promotes adipogenesis in murine and human adipose-derived stem cells. This effect is exclusive to early-differentiation-stage cells, in which the adipogenic transcription factors C/EBPδ and C/EBPβ are rapidly upregulated by IL-1β and enriched near important adipogenic genes. The pro-adipogenic, but not pro-inflammatory effect of IL-1β is potentiated by acute treatment and blocked by chronic exposure. Thus, we propose that transient postprandial IL-1β surges regulate WAT remodeling by promoting adipogenesis, whereas chronically elevated IL-1β levels in obesity blunts this physiological function.

In humans, perinatal exposure to an elevated omega-6 (n6) relative to omega-3 (n3) Fatty Acid (FA) ratio is associated with the likelihood of childhood obesity. In mice, we show perinatal exposure to excessive n6-FA programs neonatal Adipocyte Stem-like cells (ASCs) to differentiate into adipocytes with lower mitochondrial nutrient oxidation and a propensity for nutrient storage. Omega-6 FA exposure reduced fatty acid oxidation (FAO) capacity, coinciding with impaired induction of beige adipocyte regulatory factors PPARγ, PGC1α, PRDM16, and UCP1. ASCs from n6-FA exposed pups formed adipocytes with increased lipogenic genes in vitro, consistent with an in vivo accelerated adipocyte hypertrophy, greater triacylglyceride accumulation, and increased % body fat. Conversely, n6-FA exposed pups had impaired whole animal 13C-palmitate oxidation. The metabolic nuclear receptor, NR2F2, was suppressed in ASCs by excess n6-FA intake preceding adipogenesis. ASC deletion of NR2F2, prior to adipogenesis, mimicked the reduced FAO capacity observed in ASCs from n6-FA exposed pups, suggesting that NR2F2 is required in ASCs for robust beige regulator expression and downstream nutrient oxidation in adipocytes. Transiently re-activating NR2F2 with ligand prior to differentiation in ASCs from n6-FA exposed pups, restored their FAO capacity as adipocytes by increasing the PPARγ-PGC1α axis, mitochondrial FA transporter CPT1A, ATP5 family synthases, and NDUF family Complex I proteins. Our findings suggest that excessive n6-FA exposure early in life dampens an NR2F2-mediated induction of beige adipocyte regulators, resulting in metabolic programming that is shifted towards nutrient storage.

Excessive fat deposition leads to obesity and cardiovascular diseases with abnormal metabolism. Pantothenic acid (PA) is a major B vitamin required for energy metabolism. However, the effect of PA on lipid metabolism and obesity has not been explored. We investigated the effects and molecular mechanism of PA on fat accumulation as well as the influence of adipogenic marker genes in both adult male mice and primary adipocytes. First, we demonstrated that PA attenuates weight gain in mice fed high-fat diet (HFD). Besides, PA supplementation substantially improved glucose tolerance and lipid metabolic disorder in obese mice. Furthermore, PA significantly inhibited white adipose tissue (WAT) deposition as well as fat droplets visualized by magnification in both chow and HFD group. More importantly, PA obviously suppressed the mRNA levels of CD36, IL-6, and TNF-α to alleviate inflammation and reduced the levels of PPARγ, aP2, and C/EBPα genes that are related to lipid metabolism in inguinal white adipose tissue (ing-WAT) and epididymal white adipose tissue (ei-WAT). In vitro, PA supplementation showed a lower lipid droplet aggregation as well as reduced expression levels of adipogentic genes. Finally, we identified that PA inhibits the phosphorylation levels of p38 and JNK in murine primary adipocytes. Collectively, our data demonstrated for the first time that PA attenuates lipid metabolic disorder as well as fat deposition by JNK/p38 MAPK signaling pathway.

The unstable recipient conditions after fat grafting remain an obstacle for tissue volumization. The interaction between fat grafts and recipient sites is not fully understood. The authors hypothesize that recipient-derived adipocytes undergo dedifferentiation and migrate into fat grafts in tissue regeneration.

To observe the participation from recipient fat pad, the authors established a recipient adipocyte-tracing model where 0.2 mL of inguinal fat from 10 8-week-old C57BL/6 mice was grafted to 10 tamoxifen-treated AdipoqCre;mT/mG mice. Next, to evaluate the impact of physical force on recipient fat and fat graft, a murine internal expansion model was established by implanting a 1-mL internal expander on the inguinal fat pad of the lineage tracing mice that received fat graft from C57BL/6 mice. Transplanted adipose tissue was collected and analyzed by immunostaining of green fluorescent protein (GFP), tdTomato, perilipin, and CD31.

In the observing model, immunostaining revealed that both GFP+ and tdTomato + cells from the recipient fat pad presented in fat grafts. Among the GFP + cells, most of them were perilipin + adipocytes and other perilipin - cells co-expressed octamer-binding transcription factor 4, indicating dedifferentiated adipocytes. In the internal expansion model, internal expansion increased GFP + cells in fat graft. Both octamer-binding transcription factor 4-positive/GFP + (0.23 ± 0.01 versus 0.12 ± 0.04) and perilipin + /GFP + (0.17 ± 0.02 versus 0.06 ± 0.01) cells were increased in the expanded group, compared with control.

Host-derived adipocytes participate in fat graft regeneration through migration and dedifferentiation, which could be enhanced by internal expansion to increase fat graft retention rate. Further study using a larger animal model is needed, because this is a murine study.

Surgeons are encouraged to use physical expansion preconditioning of the recipient site. Subsequent and multiple fat grafting into the fat layer is encouraged to obtain satisfactory soft-tissue volumization.

Body composition impacts female fertility and there are established relationships between adipose tissue and the reproductive system. Maintaining functional adipose tissue is vital for meeting the energetic demands during the reproductive process, from ovulation to delivery and lactation. White adipose tissue (WAT) shows plastic responses to daily physiology and secretes diverse adipokines that affect the hypothalamic-pituitary-ovarian axis, but many other interorgan interactions remain to be determined. This review summarizes the current state of research on the dialogue between WAT and the female reproductive system, focusing on the impact of this crosstalk on ovarian and endometrial factors essential for fecundity.

Bone resorption by osteoclasts is a critical step in bone remodeling, a process important for maintaining bone homeostasis and repairing injured bone. We previously identified a bone marrow mesenchymal subpopulation, marrow adipogenic lineage precursors (MALPs), and showed that its production of RANKL stimulates bone resorption in young mice using Adipoq-Cre. To exclude developmental defects and to investigate the role of MALPs-derived RANKL in adult bone, we generated inducible reporter mice (Adipoq-CreER Tomato) and RANKL deficient mice (Adipoq-CreER RANKLflox/flox, iCKO). Single cell-RNA sequencing data analysis, lineage tracing, and in situ hybridization revealed that Adipoq+ cells contain not only MALPs but also late mesenchymal progenitors capable of osteogenic differentiation. However, RANKLmRNA was only detected in MALPs, but not in osteogenic cells. RANKL deficiency in MALPs induced at 3 months of age rapidly increased trabecular bone mass in long bones as well as vertebrae within 1 month due to diminished bone resorption but had no effect on the cortical bone. Ovariectomy (OVX) induced trabecular bone loss at both sites. RANKL depletion either before OVX or at 6 weeks post OVX protected and restored trabecular bone mass. Furthermore, bone healing after drill-hole injury was delayed in iCKO mice. Together, our findings demonstrate that MALPs play a dominant role in controlling trabecular bone resorption and that RANKL from MALPs is essential for trabecular bone turnover in adult bone homeostasis, postmenopausal bone loss, and injury repair.

Facial infiltrating lipomatosis (FIL) is a congenital disorder. The pathogenesis of FIL is associated with PIK3CA mutations, but the underlying mechanisms remain undetermined. We found that the adipose tissue in FIL demonstrated adipocytes hypertrophy and increased lipid accumulation. All adipose-derived mesenchymal stem cells from FIL (FIL-ADSCs) harbored PIK3CA mutations. Moreover, FIL-ADSCs exhibited a greater capacity for adipogenesis. Knockdown of PIK3CA resulted in a reduction in the adipogenic potential of FIL-ADSCs. Furthermore, WX390, a dual-target PI3K/mTOR inhibitor, was found to impede PIK3CA-mediated adipogenesis both in vivo and in vitro. RNA sequencing (RNA-seq) revealed that the expression of transient receptor potential vanilloid subtype 1 (TRPV1) was upregulated after PI3K pathway inhibition, and overexpression or activation of TRPV1 both inhibited adipogenesis. Our study showed that PIK3CA mutations promoted adipogenesis in FIL-ADSCs and this effect was achieved by suppressing TPRV1. Pathogenesis experiments suggested that WX390 may serve as an agent for the treatment of FIL.

Obesity, characterised by excessive fat accumulation, is a complex chronic condition that results from dysfunctional adipose tissue expansion due to prolonged calorie surplus. This leads to rapid adipocyte enlargement that exceeds the support capacity of the surrounding neurovascular network, resulting in increased hypoxia, inflammation, and insulin resistance. Intermittent fasting (IF), a dietary regimen that cycles between periods of fasting and eating, has emerged as an effective strategy to combat obesity and improve metabolic homeostasis by promoting healthy adipose tissue remodeling. However, the precise molecular and cellular mechanisms behind the metabolic improvements and remodeling of white adipose tissue (WAT) driven by IF remain elusive. This review aims to summarise and discuss the relationship between IF and adipose tissue remodeling and explore the potential mechanisms through which IF induces alterations in WAT. This includes several key structural changes, including angiogenesis and sympathetic innervation of WAT. We will also discuss the involvement of key signalling pathways, such as PI3K, SIRT, mTOR, and AMPK, which potentially play a crucial role in IF-mediated metabolic adaptations.

Perivascular adipose tissue (PVAT) regulates vascular tone by releasing anticontractile factors. These anticontractile factors are driven by processes downstream of adipocyte stimulation by norepinephrine; however, whether norepinephrine originates from neural innervation or other sources is unknown. The goal of this study was to test the hypothesis that neurons innervating PVAT provide the adrenergic drive to stimulate adipocytes in aortic and mesenteric perivascular adipose tissue (aPVAT and mPVAT), and white adipose tissue (WAT). Healthy male and female mice (8-13 wk) were used in all experiments. Expression of genes associated with synaptic transmission were quantified by qPCR and adipocyte activity in response to neurotransmitters and neuron depolarization was assessed in AdipoqCre+;GCaMP5g-tdTf/WT mice. Immunostaining, tissue clearing, and transgenic reporter lines were used to assess anatomical relationships between nerves and adipocytes. Although synaptic transmission component genes are expressed in adipose tissues (aPVAT, mPVAT, and WAT), strong nerve stimulation with electrical field stimulation does not significantly trigger calcium responses in adipocytes. However, norepinephrine consistently elicits strong calcium responses in adipocytes from all adipose tissues studied. Bethanechol induces minimal adipocyte responses. Imaging neural innervation using various techniques reveals that nerve fibers primarily run alongside blood vessels and rarely branch into the adipose tissue. Although nerve fibers are associated with blood vessels in adipose tissue, they demonstrate limited anatomical and functional interactions with adjacent adipocytes, challenging the concept of classical innervation. These findings dispute the significant involvement of neural input in regulating PVAT adipocyte function and emphasize alternative mechanisms governing adrenergic-driven anticontractile functions of PVAT.NEW & NOTEWORTHY This study challenges prevailing views on neural innervation in perivascular adipose tissue (PVAT) and its role in adrenergic-driven anticontractile effects on vasculature. Contrary to existing paradigms, limited anatomical and functional connections were found between PVAT nerve fibers and adipocytes, underscoring the importance of exploring alternative mechanistic pathways. Understanding the mechanisms involved in PVAT's anticontractile effects is critical for developing potential therapeutic interventions against dysregulated vascular tone, hypertension, and cardiovascular disease.

Adipose progenitor cells (APCs) are heterogeneous stromal cells and help to maintain metabolic homeostasis. However, the influence of obesity on human APC heterogeneity and the role of APC subpopulations on regulating glucose homeostasis remain unknown. Here, we find that APCs in human visceral adipose tissue contain four subsets. The composition and functionality of APCs are altered in patients with type 2 diabetes (T2D). CD9+CD55low APCs are the subset which is significantly increased in T2D patients. Transplantation of these cells from T2D patients into adipose tissue causes glycemic disturbance. Mechanistically, CD9+CD55low APCs promote T2D development through producing bioactive proteins to form a detrimental niche, leading to upregulation of adipocyte lipolysis. Depletion of pathogenic APCs by inducing intracellular diphtheria toxin A expression or using a hunter-killer peptide improves obesity-related glycemic disturbance. Collectively, our data provide deeper insights in human APC functionality and highlights APCs as a potential therapeutic target to combat T2D. All mice utilized in this study are male.

To investigate the effects of excessive light exposure during gestation on intrauterine development and early growth of neonates in rats.

Pregnant rats were randomly allocated to three groups: the constant light exposure group, non-light exposure group and control group. Blood samples were collected from the tail vein to analyze melatonin and cortisol levels. Weight, daily food and water consumption were recorded. Uterine weight, placental weight and placental diameter were measured on gestational day 19. Natural birth and neonate growth were also monitored. The expression of NR1D1(nuclear receptor subfamily 1 group D member 1) in offspring's SCN (suprachiasmatic nuclei), liver and adipose tissue was measured. Expression of NR1D1, MT1(melatonin 1 A receptor) and 11β-HSD2 (placental 11β-hydroxysteroid dehydrogenase type 2) in placenta was also measured. Finally, the expression of MT1 and 11β-HSD2 in NR1D1 siRNA transfected JEG-3 cells was evaluated.

There were no significant differences in maternal weight gain, pregnancy duration, uterine weight, placental body weight, placental diameter, fetal number among three groups. There were no significant differences in weights or lengths of offspring at birth. Compared to other two groups, constant light exposure group showed significantly more rapid growth of offspring in 21st day post-birth. The expression of NR1D1 in SCN, liver and adipose tissues of offspring was not significantly different among three groups. The maternal serum melatonin and cortisol levels of the constant light exposure group were lower and higher than other two groups, respectively. The expressions of NR1D1, MT1 and 11β-HSD2 were all decreased in placenta of the constant light exposure group. The expression of MT1 and 11β-HSD2 in JEG-3 cells were decreased after NR1D1 siRNA transfection.

Excessive light exposure during pregnancy results in elevated cortisol and reduced melatonin exposure to fetuses in uterus, potentially contributing to an accelerated early growth of offspring in rats.

Neurofibromin, coded by the NF1 tumor suppressor gene, is the main negative regulator of the RAS pathway and is frequently mutated in various cancers. Women with Neurofibromatosis Type I (NF1)-a tumor predisposition syndrome caused by a germline NF1 mutation-have an increased risk of developing aggressive breast cancer with poorer prognosis. The mechanism by which NF1 mutations lead to breast cancer tumorigenesis is not well understood. Therefore, the objective of this work was to identify stromal alterations before tumor formation that result in the increased risk and poorer outcome seen among NF1 patients with breast cancer.

To accurately model the germline monoallelic NF1 mutations in NF1 patients, we utilized an Nf1-deficient rat model with accelerated mammary development before presenting with highly penetrant breast cancer.

We identified increased collagen content in Nf1-deficient rat mammary glands before tumor formation that correlated with age of tumor onset. Additionally, gene expression analysis revealed that Nf1-deficient mature adipocytes in the rat mammary gland have increased collagen expression and shifted to a fibroblast and preadipocyte expression profile. This alteration in lineage commitment was also observed with in vitro differentiation, however, flow cytometry analysis did not show a change in mammary adipose-derived mesenchymal stem cell abundance.

Collectively, this study uncovered the previously undescribed role of Nf1 in mammary collagen deposition and regulating adipocyte differentiation. In addition to unraveling the mechanism of tumor formation, further investigation of adipocytes and collagen modifications in preneoplastic mammary glands will create a foundation for developing early detection strategies of breast cancer among NF1 patients.

Few studies are available on the relationship of androstenedione with inflammation and obesity and the effect of androstenedione and inflammation on the association between testosterone and obesity. This study intended to examine the mediation effect of inflammatory markers on the association of testosterone with obesity and the moderation effect of androstenedione on the association of testosterone with inflammation and obesity in Chinese rural men.

This cross-sectional research enrolled 2536 male rural inhabitants from the Henan Rural Cohort study. The serum concentrations of testosterone and androstenedione were determined by liquid chromatography-tandem mass spectrometry. Linear and logistic regression were used to examine the relationships between testosterone, inflammatory markers, and obesity. Mediation and moderation analyses were carried out to evaluate the potential effects of inflammatory markers on the relationship between testosterone and obesity, as well as androstenedione on the relationships of testosterone with inflammation and obesity.

After adjusting for confounding factors, the results showed that testosterone and androstenedione were negatively related to obesity, and inflammatory markers were positively associated with obesity. Besides, testosterone and androstenedione were negatively associated with inflammatory markers. Mediation analysis showed that white blood cell, neutrophil, monocyte, and high-sensitivity C-reactive protein had mediating effects on the association between testosterone and obesity. The most vital mediator was high-sensitivity C-reactive protein, and its proportion of the effect was 11.02% (defined by waist circumference), 11.15% (defined by waist-to-hip ratio), 12.92% (defined by waist-to-height ratio), and full mediating effect (defined by body mass index). Moreover, androstenedione played negative moderation effects on the associations of testosterone with inflammation and obesity.

Inflammatory markers and androstenedione were first found to have modifying effects on the association of testosterone with obesity. Higher levels of testosterone and androstenedione could reduce the inflammation level and risk of obesity, indicating their potential roles in the prevention and treatment of chronic diseases.

Obesity is a chronic disease that affects the energy balance of the whole body. In addition to increasing fat mass, tissue fibrosis occurred in white adipose tissue in obese condition. Fibrosis is the over-activation of fibroblasts leading to excessive accumulation of extracellular matrix, which could be caused by various factors, including the status of adipocytes. The morphology of adipocytes responds rapidly and dynamically to nutrient fluctuations. Adaptive hypertrophy of normal adipocytes protects peripheral organs from damage from lipotoxicity. However, the biological behavior of hypertrophic adipocytes in chronic obesity is abnormally altered. Adipocytes lead to fibrotic remodeling of the extracellular matrix by inducing unresolved chronic inflammation, persistent hypoxia, and increasing myofibroblast numbers. Moreover, adipocyte-induced fibrosis not only restricts the flexible expansion and contraction of adipose tissue but also initiates the development of various diseases through cellular autonomic and paracrine effects. Regarding anti-fibrotic therapy, dysregulated intracellular signaling and epigenetic changes represent potential candidate targets. Thus, modulation of adipocytes may provide potential therapeutic avenues for reversing pathological fibrosis in adipose tissue and achieving the anti-obesity purpose.

Central pattern of fat distribution, especially fat accumulation within the intraabdominal cavity increases risks for cardiometabolic diseases. Portal hypothesis combined with a pathological remodeling in visceral fat is considered the major etiological factor explaining the independent contribution of visceral obesity to cardiometabolic diseases. Excessive remodeling in visceral fat during development of obesity leads to dysfunctions in the depot, characterized by hypertrophy and death of adipocytes, hypoxia, inflammation, and fibrosis. Dysfunctional visceral fat secretes elevated levels of fatty acids, glycerol, and proinflammatory and profibrotic cytokines into the portal vein directly impacting the liver, the central regulator of systemic metabolism. These metabolic and endocrine products induce ectopic fat accumulation, insulin resistance, inflammation, and fibrosis in the liver, which in turn causes or exacerbates systemic metabolic derangements. Elucidation of underlying mechanisms that lead to the pathological remodeling and higher degree of dysfunctions in visceral adipose tissue is therefore, critical for the development of therapeutics to prevent deleterious sequelae in obesity. We review depot differences in metabolic and endocrine properties and expendabilities as well as underlying mechanisms that contribute to the pathophysiological aspects of visceral adiposity in cardiometabolic diseases. We also discuss impacts of different weight loss interventions on visceral adiposity and cardiometabolic diseases.

Mutations in the Trk-fused gene (TFG) cause hereditary motor and sensory neuropathy with proximal dominant involvement, which reportedly has high co-incidences with diabetes and dyslipidemia, suggesting critical roles of the TFG in metabolism as well. We found that TFG expression levels in white adipose tissues (WATs) were elevated in both genetically and diet-induced obese mice and that TFG deletion in preadipocytes from the stromal vascular fraction (SVF) markedly inhibited adipogenesis. To investigate its role in vivo, we generated tamoxifen-inducible adipocyte-specific TFG knockout (AiTFG KO) mice. While a marked down-regulation of the peroxisome proliferator-activated receptor gamma target, de novo lipogenesis (DNL), and mitochondria-related gene expressions were observed in subcutaneous WAT (scWAT) from AiTFG KO mice, these effects were blunted in SVF-derived adipocytes when the TFG was deleted after differentiation into adipocytes, implying cell nonautonomous effects. Intriguingly, expressions of thyroid hormone receptors, as well as carbohydrate responsive element-binding protein β, which mediates the metabolic actions of thyroid hormone, were drastically down-regulated in scWAT from AiTFG KO mice. Reduced DNL and thermogenic gene expressions in AiTFG KO mice might be attributable to impaired thyroid hormone action in vivo. Finally, when adipocyte TFG was deleted in either the early or the late phase of high-fat diet feeding, the former brought about an impaired expansion of epididymal WAT, whereas the latter caused prominent adipocyte cell death. TFG deletion in adipocytes markedly exacerbated hepatic steatosis in both experimental settings. Collectively, these observations indicate that the TFG plays essential roles in maintaining normal adipocyte functions, including an enlargement of adipose tissue, thyroid hormone function, and thermogenic gene expressions, and in preserving hypertrophic adipocytes.

Worldwide, childhood obesity cases continue to rise, and its prevalence is known to increase the risk of non-communicable diseases typically found in adults, such as cardiovascular disease and type 2 diabetes mellitus. Thus, comprehending its multiple causes to build healthier approaches and revert this scenario is urgent. Obesity development is strongly associated with high fructose intake since the excessive consumption of this highly lipogenic sugar leads to white fat accumulation and causes white adipose tissue (WAT) inflammation, oxidative stress, and dysregulated adipokine release. Unfortunately, the global consumption of fructose has increased dramatically in recent years, which is associated with the fact that fructose is not always evident to consumers, as it is commonly added as a sweetener in food and sugar-sweetened beverages (SSB). Therefore, here, we discuss the impact of excessive fructose intake on adipose tissue biology, its contribution to childhood obesity, and current strategies for reducing high fructose and/or free sugar intake. To achieve such reductions, we conclude that it is important that the population has access to reliable information about food ingredients via food labels. Consumers also need scientific education to understand potential health risks to themselves and their children.

White adipose tissue (WAT) development and adult homeostasis rely on distinct adipocyte progenitor cells (APCs). While adult APCs are defined early during embryogenesis and generate adipocytes after WAT organogenesis, the mechanisms underlying adult adipose lineage determination and preservation remain undefined. Here, we uncover a critical role for platelet-derived growth factor receptor beta (Pdgfrβ) in identifying the adult APC lineage. Without Pdgfrβ, APCs lose their adipogenic competency to incite fibrotic tissue replacement and inflammation. Through lineage tracing analysis, we reveal that the adult APC lineage is lost and develops into macrophages when Pdgfrβ is deleted embryonically. Moreover, to maintain the APC lineage, Pdgfrβ activation stimulates p38/MAPK phosphorylation to promote APC proliferation and maintains the APC state by phosphorylating peroxisome proliferator activated receptor gamma (Pparγ) at serine 112. Together, our findings identify a role for Pdgfrβ acting as a rheostat for adult adipose lineage confinement to prevent unintended lineage switches.

Aims: Structural analogues of bisphenol A (BPA), including bisphenol S (BPS) and bisphenol F (BPF), are emerging environmental toxicants as their presence in the environment is rising since new regulatory restrictions were placed on BPA-containing infant products. The adipogenesis-enhancing effect of bisphenols may explain the link between human exposure and metabolic disease; however, underlying molecular pathways remain unresolved. Results: Exposure to BPS, BPF, BPA, or reactive oxygen species (ROS) generators enhanced lipid droplet formation and expression of adipogenic markers after induction of differentiation in adipose-derived progenitors isolated from mice. RNAseq analysis in BPS-exposed progenitors revealed modulation in pathways regulating adipogenesis and responses to oxidative stress. ROS were higher in bisphenol-exposed cells, while cotreatment with antioxidants attenuated adipogenesis and abolished the effect of BPS. There was a loss of mitochondrial membrane potential in BPS-exposed cells and mitochondria-derived ROS contributed to the potentiation of adipogenesis by BPS and its analogues. Male mice exposed to BPS during gestation had higher whole-body adiposity, as measured by time domain nuclear magnetic resonance, while postnatal exposure had no impact on adiposity in either sex. Innovation: These findings support existing evidence showing a role for ROS in regulating adipocyte differentiation and are the first to highlight ROS as a unifying mechanism that explains the proadipogenic properties of BPA and its structural analogues. Conclusion: ROS act as signaling molecules in the regulation of adipocyte differentiation and mediate bisphenol-induced potentiation of adipogenesis. Antioxid. Redox Signal. 40, 1-15.

The ratio of free fatty acid (FFA) turnover decreases significantly with the expansion of white adipose tissue. Adipose tissue and dietary saturated fatty acid levels significantly correlate with an increase in fat cell size and number. The G0/G1 switch gene 2 increases lipid content in adipocytes and promotes adipocyte hypertrophy through the restriction of triglyceride (triacylglycerol: TAG) turnover. Hypoxia in obese adipose tissue due to hypertrophic adipocytes results in excess deposition of extracellular matrix (ECM) components. Cluster of differentiation (CD) 44, as the main receptor of the extracellular matrix component regulates cell-cell and cell-matrix interactions including diet-induced insulin resistance. Excess TAGs, sterols, and sterol esters are surrounded by the phospholipid monolayer surface and form lipid droplets (LDs). Once LDs are formed, they grow up because of the excessive amount of intracellular FFA stored and reach a final size. The ratio of FFA turnover/lipolysis decreases significantly with increases in the degree of obesity. Dysfunctional adipose tissue is unable to expand further to store excess dietary lipids, increased fluxes of plasma FFAs lead to ectopic fatty acid deposition and lipotoxicity. Reduced neo-adipogenesis and dysfunctional lipid-overloaded adipocytes are hallmarks of hypertrophic obesity linked to insulin resistance. Obesity-associated adipocyte death exhibits feature of necrosis-like programmed cell death. Adipocyte death is a prerequisite for the transition from hypertrophic to hyperplastic obesity. Increased adipocyte number in obesity has life-long effects on white adipose tissue mass. The positive correlation between the adipose tissue volume and magnetic resonance imaging proton density fat fraction estimation is used for characterization of the obesity phenotype, as well as the risk stratification and selection of appropriate treatment strategies. In obese patients with type 2 diabetes, visceral adipocytes exposed to chronic/intermittent hyperglycemia develop a new microRNAs' (miRNAs') expression pattern. Visceral preadipocytes memorize the effect of hyperglycemia via changes in miRNAs' expression profile and contribute to the progression of diabetic phenotype. Nonsteroidal anti-inflammatory drugs, metformin, and statins can be beneficial in treating the local or systemic consequences of white adipose tissue inflammation. Rapamycin inhibits leptin-induced LD formation. Collectively, in this chapter, the concept of adipose tissue remodeling in response to adipocyte death or adipogenesis, and the complexity of LD interactions with the other cellular organelles are reviewed. Furthermore, clinical perspective of fat cell turnover in obesity is also debated.

The adipose tissue organ is organised as distinct anatomical depots located all along the body axis, and it is constituted of three different types of adipocytes: white, beige and brown, which are integrated with vascular, immune, neural, and extracellular stroma cells. These distinct adipocytes serve different specialised functions. The main function of white adipocytes is to ensure healthy storage of excess nutrients/energy and its rapid mobilisation to supply the demand of energy imposed by physiological cues in other organs, whereas brown and beige adipocytes are designed for heat production through uncoupling lipid oxidation from energy production. The concerted action of the three types of adipocytes/tissues ensures an optimal metabolic status. However, when one or several of these adipose depots become dysfunctional because of sustained lipid/nutrient overload, then insulin resistance and associated metabolic complications ensue. These metabolic alterations close a vicious cycle that negatively affects the adipose tissue functionality and compromises global metabolic homeostasis. Optimising white adipose tissue expandability and ensuring its functional metabolic flexibility and/or promoting brown/beige mediated thermogenic activity are complementary strategies that counteract obesity and its associated lipotoxic metabolic effects. However, the development of these therapeutic approaches requires a deep understanding of adipose tissue in all broad aspects. In this chapter, we will discuss the characteristics of the different adipose tissue depots with respect to origins and precursors recruitment, plasticity, cellular composition, and expandability capacity potential as well as molecular and metabolic characteristic signatures in both physiological and pathophysiological conditions. Current antilipotoxic strategies for future clinical application are also discussed in this chapter.

Support for stem cell self-renewal and differentiation hinges upon the intricate microenvironment termed the stem cell 'niche'. Within the adipose tissue stem cell niche, diverse cell types, such as endothelial cells, immune cells, mural cells, and adipocytes, intricately regulate the function of adipocyte precursors. These interactions, whether direct or indirect, play a pivotal role in governing the balance between self-renewal and differentiation of adipocyte precursors into adipocytes. The mechanisms orchestrating the maintenance and coordination of this niche are still in the early stages of comprehension, despite their crucial role in regulating adipose tissue homeostasis. The complexity of understanding adipocyte precursor renewal and differentiation is amplified due to the challenges posed by the absence of suitable surface receptors for identification, limitations in creating optimal ex vivo culture conditions for expansion and constraints in conducting in vivo studies. This review delves into the current landscape of knowledge surrounding adipocyte precursors within the adipose stem cell niche. We will review the identification of adipocyte precursors, the cell-cell interactions they engage in, the factors influencing their renewal and commitment toward adipocytes and the transformations they undergo during instances of obesity.

The role of dermal white adipose tissue in regulating skin homeostasis and self-renewal processes has recently attracted interest. However, the isolation of proteins from dermal adipocytes for biochemical analysis is challenging. Here, we provide a protocol for the isolation of murine dermal adipocytes. We describe steps for inducing adipocyte-specific gene deletion, adipocyte isolation, protein purification, and western blot analysis. The reliability of the protocol is demonstrated by verifying efficient adipocyte-specific Atgl gene deletion in a tamoxifen-inducible Cre/loxP-based mouse model. For complete details on the use and execution of this protocol, please refer to Zhang et al. (2019).1.

The concept of Developmental Origin of Health and Disease (DOHaD) postulates that adult-onset metabolic disorders may originate from suboptimal conditions during critical embryonic and fetal programming windows. In particular, nutritional disturbance during key developmental stages may program the set point of adiposity and its associated metabolic diseases later in life. Numerous studies in mammals have reported that maternal obesity and the resulting accelerated growth in neonates may affect adipocyte development, resulting in persistent alterations in adipose tissue plasticity (i.e., adipocyte proliferation and storage) and adipocyte function (i.e., insulin resistance, impaired adipokine secretion, reduced thermogenesis, and higher inflammation) in a sex- and depot-specific manner. Over recent years, adipose progenitor cells (APCs) have been shown to play a crucial role in adipose tissue plasticity, essential for its development, maintenance, and expansion. In this review, we aim to provide insights into the developmental timeline of lineage commitment and differentiation of APCs and their role in predisposing individuals to obesity and metabolic diseases. We present data supporting the possible implication of dysregulated APCs and aberrant perinatal adipogenesis through epigenetic mechanisms as a primary mechanism responsible for long-lasting adipose tissue dysfunction in offspring born to obese mothers.

The moonlighting protein c-Myc is a master regulator of multiple biological processes including cell proliferation, differentiation, angiogenesis, apoptosis and metabolism. It is constitutively and aberrantly expressed in more than 70% of human cancers. Overwhelming evidence suggests that c-Myc dysregulation is involved in several inflammatory, autoimmune, metabolic and other non-cancerous diseases. In this review, we addressed the role of c-Myc in obesity. Obesity is a systemic disease, accompanied by multi-organ dysfunction apart from white adipose tissue (WAT), such as the liver, the pancreas, and the intestine. c-Myc plays a big diversity of functions regulating cellular proliferation, the maturation of progenitor cells, fatty acids (FAs) metabolism, and extracellular matrix (ECM) remodeling. Moreover, c-Myc drives the expression of a wide range of metabolic genes, modulates the inflammatory response, induces insulin resistance (IR), and contributes to the regulation of intestinal dysbiosis. Altogether, c-Myc is an interesting diagnostic tool and/or therapeutic target in order to mitigate obesity and its consequences.

We are far behind the 2025 World Health Organization (WHO) goal of a zero increase in obesity. Close to 360 million people in Latin America and the Caribbean are overweight, with the highest rates observed in the Bahamas, Mexico, and Chile. To achieve relevant progress against the obesity epidemic, scientific research is essential to establish uniform practices in the study of obesity pathophysiology (using pre-clinical and clinical models) that ensure accuracy, reproducibility, and transcendent outcomes. The present review focuses on relevant aspects of white adipose tissue (WAT) expansion, underlying mechanisms of inefficient expandability, and its repercussion in ectopic lipid accumulation in the liver during nutritional abundance. In addition, we highlight the potential role of disrupted circadian rhythm in WAT metabolism. Since genetic factors also play a key role in determining an individual's predisposition to weight gain, we describe the most relevant genes associated with obesity in the Mexican population, underlining that most of them are related to appetite control.