It is becoming increasingly clear that transcription factors operate in complex networks through thousands of genomic binding sites, many of which bind several transcription factors. However, the extent and mechanisms of crosstalk between transcription factors at these hotspots remain unclear. Using a combination of advanced proteomics and genomics approaches, we identify ∼12,000 transcription factor hotspots (∼400 bp) in the early phase of adipogenesis, and we find evidence of both simultaneous and sequential binding of transcription factors at these regions. We demonstrate that hotspots are highly enriched in large super-enhancer regions (several kilobases), which drive the early adipogenic reprogramming of gene expression. Our results indicate that cooperativity between transcription factors at the level of hotspots as well as super-enhancers is very important for enhancer activity and transcriptional reprogramming. Thus, hotspots and super-enhancers constitute important regulatory hubs that serve to integrate external stimuli on chromatin.

Lipedema is an adipofascial disorder that almost exclusively affects women. Lipedema leads to chronic pain, swelling, and other discomforts due to the bilateral and asymmetrical expansion of subcutaneous adipose tissue. Although various distinctive morphological characteristics, such as the hyperproliferation of fat cells, fibrosis, and inflammation, have been characterized in the progression of lipedema, the mechanisms underlying these changes have not yet been fully investigated. In addition, it is challenging to reduce the excessive fat in lipedema patients using conventional weight-loss techniques, such as lifestyle (diet and exercise) changes, bariatric surgery, and pharmacological interventions. Therefore, lipedema patients also go through additional psychosocial distress in the absence of permanent treatment. Research to understand the pathology of lipedema is still in its infancy, but promising markers derived from exosome, cytokine, lipidomic, and metabolomic profiling studies suggest a condition distinct from obesity and lymphedema. Although genetics seems to be a substantial cause of lipedema, due to the small number of patients involved in such studies, the extrapolation of data at a broader scale is challenging. With the current lack of etiology-guided treatments for lipedema, the discovery of new promising biomarkers could provide potential solutions to combat this complex disease. This review aims to address the morphological phenotype of lipedema fat, as well as its unclear pathophysiology, with a primary emphasis on excessive interstitial fluid, extracellular matrix remodeling, and lymphatic and vasculature dysfunction. The potential mechanisms, genetic implications, and proposed biomarkers for lipedema are further discussed in detail. Finally, we mention the challenges related to lipedema and emphasize the prospects of technological interventions to benefit the lipedema community in the future.

Transcription factors have recently been shown to colocalize in hotspot regions of the genome, which are further clustered into super-enhancers. However, the detailed molecular organization of transcription factors at hotspot regions is poorly defined. Here, we have used digital genomic footprinting to precisely define factor localization at a genome-wide level during the early phase of 3T3-L1 adipocyte differentiation, which allows us to obtain detailed molecular insight into how transcription factors target hotspots. We demonstrate the formation of ATF-C/EBP heterodimers at a composite motif on chromatin, and we suggest that this may be a general mechanism for integrating external signals on chromatin. Furthermore, we find evidence of extensive recruitment of transcription factors to hotspots through alternative mechanisms not involving their known motifs and demonstrate that these alternative binding events are functionally important for hotspot formation and activity. Taken together, these findings provide a framework for understanding transcription factor cooperativity in hotspots.

Metabolic syndrome (MetS), characterized by obesity, insulin resistance, dyslipidemia, and hypertension, is a growing global health concern. This review examines the relationship between adipose tissue insulin resistance (AT-IR) and MetS. Adipose tissue functions beyond energy storage as an endocrine organ that regulates metabolism through hormone and cytokine secretion. When adipose tissue becomes insulin resistant, it contributes to systemic metabolic dysfunction through impaired glucose uptake and dysregulated adipokine production. This creates a bidirectional relationship where AT-IR promotes MetS development, while MetS-associated inflammation further worsens adipose insulin sensitivity. Key mechanisms include inflammatory signaling, altered adipokine profile, and mitochondrial dysfunction. Understanding these interactions offers therapeutic opportunities, as targeting adipose tissue function may provide novel approaches for MetS treatment. This review synthesizes current evidence on AT-IR-MetS interactions and discusses therapeutic implications and future research directions.

Understanding the mammalian energy balance can pave the way for future therapeutics that enhance energy expenditure as an anti-obesity and anti-diabetic strategy. Several studies showed that brown adipose tissue activity increases daily energy expenditure. However, the size and activity of brown adipose tissue is reduced in individuals with obesity and type two diabetes. Humans have an abundance of functionally similar beige adipocytes that have the potential to contribute to increased energy expenditure. This makes beige adipocytes a promising target for metabolic disease therapies. While brown adipocytes tend to be stable, beige adipocytes have a high level of plasticity that allows for the rapid and dynamic induction of thermogenesis by external stimuli such as low environmental temperatures. This means that after browning stimuli have been withdrawn beige adipocytes quickly transition back to their white adipose state. The detailed molecular mechanisms regulating beige adipocytes development, function, and reversibility are not fully understood. The goal of this review is to give a comprehensive overview of beige fat development and origins, along with the transcriptional and epigenetic programs that lead to beige fat formation, and subsequent thermogenesis in humans. An improved understanding of the molecular pathways of beige adipocyte plasticity will enable us to selectively manipulate beige cells to induce and maintain their thermogenic output thus improving the whole-body energy homeostasis.

Since the formation of amyloid structures from proteins was recognized in numerous diseases, many efforts have been devoted to the task of finding effective anti-amyloidogenic compounds. In a number of these investigations, the existence of “generic” compounds is implicitly acknowledged. Curcumin seems to be one of these compounds, possessing key structural components effective toward fibrillation prevention, and its anti-amyloidogenic property has been reported for a number of model and disease-related proteins such as lysozyme and alpha-synuclein. In this study, insulin amyloid formation has been shown to be effectively influenced by micromolar concentrations of curcumin. Under amyloidogenic conditions (pH 2.5 and 37 °C), the compound was observed to inhibit fibril formation of insulin in a dose-dependent manner. Moreover, addition of curcumin to the protein incubated under such conditions at different time points resulted in reduced amounts of final fibrils. Disaggregation of pre-formed fibrils was also observed upon addition of curcumin, as well as reduction in final fibril amounts after seeding. Overall, this compound appears to be able to interact with native, intermediate and fibrillar forms. Docking experiments suggest a potential interacting site with the B-chain of insulin, as well as the possibility for beta-sheet breaker activity.