Tag Archives: Adipose

Pivotal Role of O-GlcNAc Modification in Cold-Induced Thermogenesis by Brown Adipose Tissue Through Mitochondrial Biogenesis

Adipose tissues considerably influence metabolic homeostasis, and both white (WAT) and brown (BAT) adipose tissue play significant roles in lipid and glucose metabolism. O-linked N-acetylglucosamine (O-GlcNAc) modification is characterized by the addition of N-acetylglucosamine to various proteins by O-GlcNAc transferase (Ogt), subsequently modulating various cellular processes. However, little is known about the role of O-GlcNAc modification in adipose tissues. Here, we report the critical role of O-GlcNAc modification in cold-induced thermogenesis. Deletion of Ogt in WAT and BAT using adiponectin promoter–driven Cre recombinase resulted in severe cold intolerance with decreased uncoupling protein 1 (Ucp1) expression. Furthermore, Ogt deletion led to decreased mitochondrial protein expression in conjunction with decreased peroxisome proliferator–activated receptor coactivator 1-α protein expression. This phenotype was further confirmed by deletion of Ogt in BAT using Ucp1 promoter–driven Cre recombinase, suggesting that O-GlcNAc modification in BAT is responsible for cold-induced thermogenesis. Hypothermia was significant under fasting conditions. This effect was mitigated after normal diet consumption but not after consumption of a fatty acid–rich ketogenic diet lacking carbohydrates, suggesting impaired diet-induced thermogenesis, particularly by fat. In conclusion, O-GlcNAc modification is essential for cold-induced thermogenesis and mitochondrial biogenesis in BAT. Glucose flux into BAT may be a signal to maintain BAT physiological responses.

Diabetes Journal current issue





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VEGF-A-Expressing Adipose Tissue Shows Rapid Beiging and Enhanced Survival After Transplantation and Confers IL-4-Independent Metabolic Improvements

Adipocyte-derived vascular endothelial growth factor-A (VEGF-A) plays a crucial role in angiogenesis and contributes to adipocyte function and systemic metabolism, such as insulin resistance, chronic inflammation, and beiging of subcutaneous adipose tissue. Using a doxycycline-inducible adipocyte-specific VEGF-A–overexpressing mouse model, we investigated the dynamics of local VEGF-A effects on tissue beiging of adipose tissue transplants. VEGF-A overexpression in adipocytes triggers angiogenesis. We also observed a rapid appearance of beige fat cells in subcutaneous white adipose tissue as early as 2 days postinduction of VEGF-A. In contrast to conventional cold-induced beiging, VEGF-A–induced beiging is independent of interleukin-4. We subjected metabolically healthy VEGF-A–overexpressing adipose tissue to autologous transplantation. Transfer of subcutaneous adipose tissues taken from VEGF-A–overexpressing mice into diet-induced obese mice resulted in systemic metabolic benefits, associated with improved survival of adipocytes and a concomitant reduced inflammatory response. These effects of VEGF-A are tissue autonomous, inducing white adipose tissue beiging and angiogenesis within the transplanted tissue. Our findings indicate that manipulation of adipocyte functions with a bona fide angiogenic factor, such as VEGF-A, significantly improves the survival and volume retention of fat grafts and can convey metabolically favorable properties on the recipient on the basis of beiging.

Diabetes Journal current issue





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Inhibition of Gastric Inhibitory Polypeptide Receptor Signaling in Adipose Tissue Reduces Insulin Resistance and Hepatic Steatosis in High-Fat Diet-Fed Mice

Gastric inhibitory polypeptide receptor (GIPR) directly induces energy accumulation in adipose tissue in vitro. However, the importance of the direct effect of GIPR signaling on adipose tissue in vivo remains unclear. In the current study, we generated adipose tissue–specific GIPR knockout (GIPRadipo–/–) mice and investigated the direct actions of GIP in adipose tissue. Under high-fat diet (HFD)-fed conditions, GIPRadipo–/– mice had significantly lower body weight and lean body mass compared with those in floxed GIPR (GIPRfl/fl) mice, although the fat volume was not significantly different between the two groups. Interestingly, insulin resistance, liver weight, and hepatic steatosis were reduced in HFD-fed GIPRadipo–/– mice. Plasma levels of interleukin-6 (IL-6), a proinflammatory cytokine that induces insulin resistance, were reduced in HFD-fed GIPRadipo–/– mice compared with those in HFD-fed GIPRfl/fl mice. Suppressor of cytokine signaling 3 (SOCS3) signaling is located downstream of the IL-6 receptor and is associated with insulin resistance and hepatic steatosis. Expression levels of SOCS3 mRNA were significantly lower in adipose and liver tissues of HFD-fed GIPRadipo–/– mice compared with those of HFD-fed GIPRfl/fl mice. Thus, GIPR signaling in adipose tissue plays a critical role in HFD-induced insulin resistance and hepatic steatosis in vivo, which may involve IL-6 signaling.

Diabetes Journal current issue





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Deletion of CD1d in Adipocytes Aggravates Adipose Tissue Inflammation and Insulin Resistance in Obesity

Adipose tissue inflammation is an important factor in obesity that promotes insulin resistance. Among various cell types in adipose tissue, immune cells actively regulate inflammatory responses and affect whole-body energy metabolism. In particular, invariant natural killer T (iNKT) cells contribute to mitigating dysregulation of systemic energy homeostasis by counteracting obesity-induced inflammation in adipose tissue. However, the molecular mechanisms by which adipose iNKT cells become activated and mediate anti-inflammatory roles in obese adipose tissue have not been thoroughly understood yet. In the current study, we demonstrate that adipocyte CD1d plays a key role in the stimulation of adipose iNKT cells, leading to anti-inflammatory responses in high-fat diet (HFD)–fed mice. Accordingly, adipocyte-specific CD1d-knockout (CD1dADKO) mice showed reduced numbers of iNKT cells in adipose tissues and decreased responses to α-galactosylceramide–induced iNKT cell activation. Additionally, HFD-fed CD1dADKO mice revealed reduced interleukin-4 expression in adipose iNKT cells and aggravated adipose tissue inflammation and insulin resistance. Collectively, these data suggest that adipocytes could selectively stimulate adipose iNKT cells to mediate anti-inflammatory responses and attenuate excess proinflammatory responses in obese adipose tissue.

Diabetes Journal current issue





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Role of Adipose Tissue Insulin Resistance in the Natural History of Type 2 Diabetes: Results From the San Antonio Metabolism Study

In the transition from normal glucose tolerance (NGT) to type 2 diabetes mellitus (T2DM), the role of β-cell dysfunction and peripheral insulin resistance (IR) is well established. However, the impact of dysfunctional adipose tissue has not been fully elucidated. The aim of this study was to evaluate the role of resistance to the antilipolytic effect of insulin (adipose tissue IR [Adipo-IR]) in a large group of subjects with NGT, impaired glucose tolerance (IGT), and T2DM. Three hundred two subjects with varying glucose tolerance received an oral glucose tolerance test (OGTT) and euglycemic insulin clamp. We evaluated Adipo-IR (fasting and mean OGTT plasma free fatty acid [FFA] x insulin concentrations), peripheral IR (1/[Matsuda index] and (M/I)–1 value), and β-cell function (calculated as the ratio of the increment in plasma insulin to glucose [OGTT/IR (I/G ÷ IR)]). Fasting Adipo-IR was increased twofold in obese subjects with NGT and IGT versus lean subjects with NGT (8.0 ± 1.1 and 9.2 ± 0.7 vs. 4.1 ± 0.3, respectively) and threefold in subjects with T2DM (11.9 ± 0.6; P < 0.001). Progressive decline in I/G ÷ IR was associated with a progressive impairment in FFA suppression during OGTT, whereas the rise in mean plasma glucose concentration only became manifest when subjects became overtly diabetic. The progressive decline in β-cell function that begins in individuals with NGT is associated with a progressive increase in FFA and fasting Adipo-IR.

Diabetes Journal current issue





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Lack of CUL4B in Adipocytes Promotes PPAR{gamma}-Mediated Adipose Tissue Expansion and Insulin Sensitivity

Obesity and obesity-associated diseases are linked to dysregulation of the peroxisome proliferator–activated receptor (PPAR) signaling pathway. Identification of the factors that regulate PPAR expression and activity is crucial for combating obesity. However, the ubiquitin E3 ligases that target PPAR for proteasomal degradation have been rarely identified, and their functions in vivo have not been characterized. Here we report that CUL4B-RING E3 ligase (CRL4B) negatively regulates PPAR by promoting its polyubiquitination and proteasomal degradation. Depletion of CUL4B led to upregulation of PPAR-regulated genes and facilitated adipogenesis. Adipocyte-specific Cul4b knockout (AKO) mice being fed a high-fat diet exhibited increased body fat accumulation that was mediated by increased adipogenesis. However, AKO mice showed improved metabolic phenotypes, including increased insulin sensitivity and glucose tolerance. Correspondingly, there was a decreased inflammatory response in adipose tissues of AKO mice. Genetic inhibition of CUL4B thus appears to phenocopy the beneficial effects of PPAR agonists. Collectively, this study establishes a critical role of CRL4B in the regulation of PPAR stability and insulin sensitivity and suggests that CUL4B could be a potential therapeutic target for combating obesity and metabolic syndromes.

Diabetes Journal current issue





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Impact of Perturbed Pancreatic {beta}-Cell Cholesterol Homeostasis on Adipose Tissue and Skeletal Muscle Metabolism

Elevated pancreatic β-cell cholesterol levels impair insulin secretion and reduce plasma insulin levels. This study establishes that low plasma insulin levels have a detrimental effect on two major insulin target tissues: adipose tissue and skeletal muscle. Mice with increased β-cell cholesterol levels were generated by conditional deletion of the ATP-binding cassette transporters, ABCA1 and ABCG1, in β-cells (β-DKO mice). Insulin secretion was impaired in these mice under basal and high-glucose conditions, and glucose disposal was shifted from skeletal muscle to adipose tissue. The β-DKO mice also had increased body fat and adipose tissue macrophage content, elevated plasma interleukin-6 and MCP-1 levels, and decreased skeletal muscle mass. They were not, however, insulin resistant. The adipose tissue expansion and reduced skeletal muscle mass, but not the systemic inflammation or increased adipose tissue macrophage content, were reversed when plasma insulin levels were normalized by insulin supplementation. These studies identify a mechanism by which perturbation of β-cell cholesterol homeostasis and impaired insulin secretion increase adiposity, reduce skeletal muscle mass, and cause systemic inflammation. They further identify β-cell dysfunction as a potential therapeutic target in people at increased risk of developing type 2 diabetes.

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Ionizing Radiation Potentiates High-Fat Diet-Induced Insulin Resistance and Reprograms Skeletal Muscle and Adipose Progenitor Cells

Exposure to ionizing radiation increases the risk of chronic metabolic disorders such as insulin resistance and type 2 diabetes later in life. We hypothesized that irradiation reprograms the epigenome of metabolic progenitor cells, which could account for impaired metabolism after cancer treatment. C57Bl/6 mice were treated with a single dose of irradiation and subjected to high-fat diet (HFD). RNA sequencing and reduced representation bisulfite sequencing were used to create transcriptomic and epigenomic profiles of preadipocytes and skeletal muscle satellite cells collected from irradiated mice. Mice subjected to total body irradiation showed alterations in glucose metabolism and, when challenged with HFD, marked hyperinsulinemia. Insulin signaling was chronically disrupted in skeletal muscle and adipose progenitor cells collected from irradiated mice and differentiated in culture. Epigenomic profiling of skeletal muscle and adipose progenitor cells from irradiated animals revealed substantial DNA methylation changes, notably for genes regulating the cell cycle, glucose/lipid metabolism, and expression of epigenetic modifiers. Our results show that total body irradiation alters intracellular signaling and epigenetic pathways regulating cell proliferation and differentiation of skeletal muscle and adipose progenitor cells and provide a possible mechanism by which irradiation used in cancer treatment increases the risk for metabolic disease later in life.

Diabetes Journal current issue





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ALOX5AP Overexpression in Adipose Tissue Leads to LXA4 Production and Protection Against Diet-Induced Obesity and Insulin Resistance

Eicosanoids, such as leukotriene B4 (LTB4) and lipoxin A4 (LXA4), may play a key role during obesity. While LTB4 is involved in adipose tissue inflammation and insulin resistance, LXA4 may exert anti-inflammatory effects and alleviate hepatic steatosis. Both lipid mediators derive from the same pathway, in which arachidonate 5-lipoxygenase (ALOX5) and its partner, arachidonate 5-lipoxygenase–activating protein (ALOX5AP), are involved. ALOX5 and ALOX5AP expression is increased in humans and rodents with obesity and insulin resistance. We found that transgenic mice overexpressing ALOX5AP in adipose tissue had higher LXA4 rather than higher LTB4 levels, were leaner, and showed increased energy expenditure, partly due to browning of white adipose tissue (WAT). Upregulation of hepatic LXR and Cyp7a1 led to higher bile acid synthesis, which may have contributed to increased thermogenesis. In addition, transgenic mice were protected against diet-induced obesity, insulin resistance, and inflammation. Finally, treatment of C57BL/6J mice with LXA4, which showed browning of WAT, strongly suggests that LXA4 is responsible for the transgenic mice phenotype. Thus, our data support that LXA4 may hold great potential for the future development of therapeutic strategies for obesity and related diseases.

Diabetes Journal current issue





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The Multifaceted Roles of Adipose Tissue–Therapeutic Targets for Diabetes and Beyond: The 2015 Banting Lecture

The Banting Medal for Scientific Achievement is the highest scientific award of the American Diabetes Association (ADA). Given in memory of Sir Frederick Banting, one of the key investigators in the discovery of insulin, the Banting Medal is awarded annually for scientific excellence, recognizing significant long-term contributions to the understanding, treatment, or prevention of diabetes. Philipp E. Scherer, PhD, of the Touchstone Diabetes Center, The University of Texas Southwestern Medical Center, Dallas, TX, received the prestigious award at the ADA’s 75th Scientific Sessions, 5–9 June 2015, in Boston, MA. He presented the Banting Lecture, “The Multifaceted Roles of Adipose Tissue—Therapeutic Targets for Diabetes and Beyond,” on Sunday, 7 June 2015.

A number of different cell types contribute to the cellular architecture of adipose tissue. Although the adipocyte is functionally making important contributions to systemic metabolic homeostatis, several additional cell types contribute a supportive role to bestow maximal flexibility on the tissue with respect to many biosynthetic and catabolic processes, depending on the metabolic state. These cells include vascular endothelial cells, a host of immune cells, and adipocyte precursor cells and fibroblasts. Combined, these cell types give rise to a tissue with remarkable flexibility with respect to expansion and contraction, while optimizing the ability of the tissue to act as an endocrine organ through the release of many protein factors, critically influencing systemic lipid homeostasis and biochemically contributing many metabolites. Using an example from each of these categories—adiponectin as a key adipokine, sphingolipids as critical mediators of insulin sensitivity, and uridine as an important metabolite contributed by the adipocyte to the systemic pool—I will discuss the emerging genesis of the adipocyte over the past 20 years from metabolic bystander to key driver of metabolic flexibility.

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