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JCEM Case Reports May 2023Lipodystrophy syndromes are rare metabolic disorders characterized by local or generalized loss of adipose tissue, resulting in insulin resistance, dyslipidemia, and...
Lipodystrophy syndromes are rare metabolic disorders characterized by local or generalized loss of adipose tissue, resulting in insulin resistance, dyslipidemia, and cosmetic disfiguration. The lipodystrophic phenotype is highly variable, with partial lipodystrophy often missed or misdiagnosed as other diseases from a lack of a proper physical examination and low physician awareness. Correct diagnosis is important for optimal treatment and follow-up strategies in these patients. The use of GLP-1 analogs has not been systematically evaluated in lipodystrophy and could be a potential precision medicine therapy. We aim to make the reader, particularly generalists or endocrinologists outside of tertiary referral centers, aware of the presentation and clinical features of partial lipodystrophy, emphasize the role of a full physical examination in diagnosis, and discuss therapeutic options, including GLP-1-based glycemic management illustrated by our clinical case.
PubMed: 37313426
DOI: 10.1210/jcemcr/luad066 -
Experimental Gerontology Jul 2023Aging is one of the primary risk factors for the development of type 2 diabetes and cardiovascular disease, and regular physical activity can help to delay, prevent, or... (Review)
Review
Aging is one of the primary risk factors for the development of type 2 diabetes and cardiovascular disease, and regular physical activity can help to delay, prevent, or manage the onset and development of many chronic diseases present in older adults. Brown adipose tissue (BAT) is thermogenic tissue that protects against age-related disease, but BAT activity decreases with age. In this review, we discuss how aging contributes to impaired BAT function by inducing a 'whitening' of the BAT and altering beta 3 adrenergic receptor (βAR) signaling, uncoupling protein 1 (UCP1) gene expression, and mitochondria respiration, and potential mechanisms for exercise to counteract the effects of aging on BAT.
Topics: Humans; Aged; Adipose Tissue, Brown; Diabetes Mellitus, Type 2; Thermogenesis; Exercise
PubMed: 37224933
DOI: 10.1016/j.exger.2023.112218 -
Adipocyte Dec 2023Adipokines are proteins secreted by adipose tissue to regulate glucolipid metabolism and play vital roles in our body. Different adipokines have more than one endocrine...
Adipokines are proteins secreted by adipose tissue to regulate glucolipid metabolism and play vital roles in our body. Different adipokines have more than one endocrine function and be divided into several different categories according to their functions, including adipokines involved in glucolipid metabolism, the inflammatory response, insulin action, activation of brown adipose tissue (BAT) and appetite regulation. Multiple adipokines interact with each other to regulate metabolic processes. Based on the recent progress of adipokine research, this article discusses the role and mechanism of various adipokines in glucolipid metabolism, which may provide new ideas for understanding the pathogenesis and improving the treatment of various metabolic diseases.
Topics: Adipokines; Glucose; Lipid Metabolism; Adipose Tissue; Adipose Tissue, Brown; Energy Metabolism; Leptin
PubMed: 37077042
DOI: 10.1080/21623945.2023.2202976 -
Antioxidants (Basel, Switzerland) Jul 2023White and brown adipose tissues are organized to form a real organ, the adipose organ, in mice and humans. White adipocytes of obese animals and humans are hypertrophic.... (Review)
Review
White and brown adipose tissues are organized to form a real organ, the adipose organ, in mice and humans. White adipocytes of obese animals and humans are hypertrophic. This condition is accompanied by a series of organelle alterations and stress of the endoplasmic reticulum. This stress is mainly due to reactive oxygen species activity and accumulation, lending to NLRP3 inflammasome activation. This last causes death of adipocytes by pyroptosis and the formation of large cellular debris that must be removed by macrophages. During their chronic scavenging activity, macrophages produce several secretory products that have collateral consequences, including interference with insulin receptor activity, causing insulin resistance. The latter is accompanied by an increased noradrenergic inhibitory innervation of Langerhans islets with de-differentiation of beta cells and type 2 diabetes. The whitening of brown adipocytes could explain the different critical death size of visceral adipocytes and offer an explanation for the worse clinical consequence of visceral fat accumulation. White to brown transdifferentiation has been proven in mice and humans. Considering the energy-dispersing activity of brown adipose tissue, transdifferentiation opens new therapeutic perspectives for obesity and related disorders.
PubMed: 37507987
DOI: 10.3390/antiox12071449 -
Cell Communication and Signaling : CCS Oct 2023The abnormal lipid and glucose metabolisms are linked to the metabolic disorders, tumorigenesis, and fibrotic diseases, which attracts the increasing attention to find... (Review)
Review
The abnormal lipid and glucose metabolisms are linked to the metabolic disorders, tumorigenesis, and fibrotic diseases, which attracts the increasing attention to find out the key molecules involved in the lipid and glucose metabolism as the possible therapeutic targets on these diseases. A transcriptional factor Twist1 has been associated with not only the embryonic development, cancer, and fibrotic diseases, but also the regulation of lipid and glucose metabolism. In this review, we will discuss the roles and mechanisms of Twist1 in the obesity-associated white adipose tissue inflammation and insulin resistance, brown adipose tissue metabolism, fatty acid oxidation, and glucose metabolism in skeletal muscle to provide a rational perspective to consider Twist1 as a potential treatment target in clinic. Video Abstract.
Topics: Humans; Muscle, Skeletal; Lipid Metabolism; Inflammation; Insulin Resistance; Glucose; Lipids
PubMed: 37784111
DOI: 10.1186/s12964-023-01262-6 -
Frontiers in Endocrinology 2024
Topics: Oocytes; Aging
PubMed: 38298380
DOI: 10.3389/fendo.2024.1361115 -
Cells Dec 2023Sirtuins (SIRT1-7 in mammals) are a family of NAD+-dependent lysine deacetylases and deacylases that regulate diverse biological processes, including metabolism, stress... (Review)
Review
Sirtuins (SIRT1-7 in mammals) are a family of NAD+-dependent lysine deacetylases and deacylases that regulate diverse biological processes, including metabolism, stress responses, and aging. SIRT7 is the least well-studied member of the sirtuins, but accumulating evidence has shown that SIRT7 plays critical roles in the regulation of glucose and lipid metabolism by modulating many target proteins in white adipose tissue, brown adipose tissue, and liver tissue. This review focuses on the emerging roles of SIRT7 in glucose and lipid metabolism in comparison with SIRT1 and SIRT6. We also discuss the possible implications of SIRT7 inhibition in the treatment of metabolic diseases such as type 2 diabetes and obesity.
Topics: Animals; Lipid Metabolism; Glucose; Sirtuin 1; Diabetes Mellitus, Type 2; Hydrolases; Sirtuins; Mammals
PubMed: 38201252
DOI: 10.3390/cells13010048 -
Nature Metabolism Aug 2023Activation of brown adipose tissue (BAT) in humans is a strategy to treat obesity and metabolic disease. Here we show that the serotonin transporter (SERT), encoded by...
Activation of brown adipose tissue (BAT) in humans is a strategy to treat obesity and metabolic disease. Here we show that the serotonin transporter (SERT), encoded by SLC6A4, prevents serotonin-mediated suppression of human BAT function. RNA sequencing of human primary brown and white adipocytes shows that SLC6A4 is highly expressed in human, but not murine, brown adipocytes and BAT. Serotonin decreases uncoupled respiration and reduces uncoupling protein 1 via the 5-HT receptor. SERT inhibition by the selective serotonin reuptake inhibitor (SSRI) sertraline prevents uptake of extracellular serotonin, thereby potentiating serotonin's suppressive effect on brown adipocytes. Furthermore, we see that sertraline reduces BAT activation in healthy volunteers, and SSRI-treated patients demonstrate no F-fluorodeoxyglucose uptake by BAT at room temperature, unlike matched controls. Inhibition of BAT thermogenesis may contribute to SSRI-induced weight gain and metabolic dysfunction, and reducing peripheral serotonin action may be an approach to treat obesity and metabolic disease.
Topics: Humans; Mice; Animals; Adipose Tissue, Brown; Serotonin; Sertraline; Serotonin Plasma Membrane Transport Proteins; Obesity; Thermogenesis; Metabolic Diseases
PubMed: 37537371
DOI: 10.1038/s42255-023-00839-2 -
Research Square Dec 2023Adipose tissue, which is crucial for the regulation of energy within the body, contains both white and brown adipocytes. White adipose tissue (WAT) primarily stores...
Adipose tissue, which is crucial for the regulation of energy within the body, contains both white and brown adipocytes. White adipose tissue (WAT) primarily stores energy, while brown adipose tissue (BAT) plays a critical role in energy dissipation as heat, offering potential for therapies aimed at enhancing metabolic health. Regulation of the RhoA/ROCK pathway is crucial for appropriate specification, differentiation and maturation of both white and brown adipocytes. However, our knowledge of how this pathway is controlled within specific adipose depots remains unclear, and to date a RhoA regulator that selectively controls adipocyte browning has not been identified. Our study shows that expression of GRAF1, a RhoGAP highly expressed in metabolically active tissues, closely correlates with brown adipocyte differentiation in culture and in vivo. Mice with either global or adipocyte-specific GRAF1 deficiency exhibit impaired BAT maturation, reduced capacity for WAT browning, and compromised cold-induced thermogenesis. Moreover, defects in differentiation of mouse or human GRAF1-deficient brown preadipocytes can be rescued by treatment with a Rho kinase inhibitor. Collectively, these studies indicate that GRAF1 can selectively induce brown and beige adipocyte differentiation and suggest that manipulating GRAF1 activity may hold promise for the future treatment of diseases related to metabolic dysfunction.
PubMed: 38196614
DOI: 10.21203/rs.3.rs-3740465/v1 -
Molecular Metabolism Aug 2023Adipogenesis is key to maintaining organism-wide energy balance and healthy metabolic phenotype, making it critical to thoroughly comprehend its molecular regulation in...
Adipogenesis is key to maintaining organism-wide energy balance and healthy metabolic phenotype, making it critical to thoroughly comprehend its molecular regulation in humans. By single-nuclei RNA-sequencing (snRNA-seq) of over 20,000 differentiating white and brown preadipocytes, we constructed a high-resolution temporal transcriptional landscape of human white and brown adipogenesis. White and brown preadipocytes were isolated from a single individual's neck region, thereby eliminating inter-subject variability across two distinct lineages. These preadipocytes were also immortalized to allow for controlled, in vitro differentiation, allowing sampling of distinct cellular states across the spectrum of adipogenic progression. Pseudotemporal cellular ordering revealed the dynamics of ECM remodeling during early adipogenesis, and lipogenic/thermogenic response during late white/brown adipogenesis. Comparison with adipogenic regulation in murine models Identified several novel transcription factors as potential targets for adipogenic/thermogenic drivers in humans. Among these novel candidates, we explored the role of TRPS1 in adipocyte differentiation and showed that its knockdown impairs white adipogenesis in vitro. Key adipogenic and lipogenic markers revealed in our analysis were applied to analyze publicly available scRNA-seq datasets; these confirmed unique cell maturation features in recently discovered murine preadipocytes, and revealed inhibition of adipogenic expansion in humans with obesity. Overall, our study presents a comprehensive molecular description of both white and brown adipogenesis in humans and provides an important resource for future studies of adipose tissue development and function in both health and metabolic disease state.
Topics: Humans; Animals; Mice; Adipogenesis; RNA-Seq; Adipose Tissue, Brown; Adipose Tissue, White; Cell Differentiation; Repressor Proteins
PubMed: 37286033
DOI: 10.1016/j.molmet.2023.101746