ResearchPad - obesity-studies https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Trajectories of early to mid-life adulthood BMI and incident diabetes: the China Health and Nutrition Survey]]> https://www.researchpad.co/article/elastic_article_9093 This longitudinal study aims to characterize distinct body mass index (BMI) trajectories during early to mid-life adulthood and to explore the association between BMI change from young adulthood to midlife and incident diabetes.Research design and methodsThis study included 7289 adults who had repeatedly measured BMI 3–9 times during 1989–2011 and information on incident diabetes. Latent class growth mixed model (LCGMM) was used to identify different BMI trajectories. Cox proportional hazard models were used to investigate the association between the trajectory group membership and incident hyperglycemia, adjusting for covariates. The hyperglycemia group included individuals with prediabetes or diabetes. The model-estimated BMI levels and slopes were calculated at each age point in 1-year intervals according to the model parameters and their first derivatives, respectively. Logistic regression analyses were used to examine the association of model-estimated levels and slopes of BMI at each age point with incident hyperglycemia. The area under the curve (AUC) was computed from longitudinal growth curve models during the follow-up for each individual. Prior to the logistic regression analyses, quartiles of total, baseline, and incremental AUC values were calculated.ResultsThree distinct trajectories were characterized by LCGMM, comprising of low-increasing group (n=5136), medium-increasing group (n=1914), and high-increasing group (n=239). Compared with the low-increasing group, adjusted HRs and 95% CIs were 1.21 (0.99 to 1.48) and 1.56 (1.06 to 2.30) for the medium-increasing and the high-increasing group, respectively. The adjusted standardized ORs of model-estimated BMI levels increased among 20–50 years, ranging from 0.98 (0.87 to 1.10) to 1.19 (1.08 to 1.32). The standardized ORs of level-adjusted linear slopes increased gradually from 1.30 (1.16 to 1.45) to 1.42 (1.21 to 1.67) during 20–29 years, then decreased from 1.41 (1.20 to 1.66) to 1.20 (1.08 to 1.33) during 30–43 years, and finally increased to 1.20 (1.04 to 1.38) until 50 years. The fourth quartile of incremental AUC (OR=1.31, 95% CI 1.03 to 1.66) was significant compared with the first quartile, after adjustment for covariates.ConclusionsThese findings indicate that the BMI trajectories during early adulthood were significantly associated with later-life diabetes. Young adulthood is a crucial period for the development of diabetes, which has implications for early prevention. ]]> <![CDATA[Enrichment of Tc1 cells and T cell resistance to suppression are associated with dysglycemia in the visceral fat in human obesity]]> https://www.researchpad.co/article/N27afc553-0021-4237-b186-f7fbb347e9b5 Insulin resistance, defined as tissue inflammation leading to type 2 diabetes, is a feature of obesity. The immune system has been implicated in its pathogenesis, but the role of adaptive immunity in humans remains uncertain. Here, we aim to determine whether specific phenotypic and functional properties of visceral adipose tissue (VAT)-derived CD4 conventional T cells (Tconv) and CD8 T cells are associated with dysglycemia in human obesity.Research design and methodsPeripheral blood and the stromal vascular fraction of obese patients without dysglycemia (n=23), with impaired fasting glucose or type 2 diabetes (n=17), and non-diabetic lean controls (n=11) were studied. Characterization of memory, activation profile, cytokine production, proliferative capacity, cytotoxic potential and transforming growth factor-β-mediated suppression of CD4 Tconv and CD8 T cells was performed. Correlation between anthropometric/metabolic parameters and VAT-derived T cell subsets was determined.ResultsIn the VAT of the overall obese population, reduced frequency of interferon-γ-producing or tumor necrosis factor-α-producing CD4 (ie, T helper 1, Th1) and CD8 (ie, cytotoxic type 1, Tc1) T cells, as well as interleukin-17-producing CD8 T cells (ie, Tc17), was evident when compared with lean controls. However, enrichment of Tc1 cells, together with the impaired ability of CD4 and CD8 T cells to be suppressed, distinguished the visceral fat of obese patients with dysglycemia from the one of non-diabetic obese patients. Moreover, accumulation of Th1 and Tc1 cells in the VAT correlated with anthropometric and metabolic parameters.ConclusionsHere, we define the VAT-specific characteristics of T cells in human obesity, showing that accumulation of Tc1 cells and T cell resistance to suppression can be harmful to the development of obesity-induced diabetes. These findings open new directions to investigate immunological targets in the obesity setting. ]]> <![CDATA[Proglucagon peptide secretion profiles in type 2 diabetes before and after bariatric surgery: 1-year prospective study]]> https://www.researchpad.co/article/N5d3365c4-9830-4d01-a239-7d336c5820f0

Introduction

Hyperglucagonemia is a key pathophysiological driver of type 2 diabetes. Although Roux-en-Y gastric bypass (RYGB) is a highly effective treatment for diabetes, it is presently unclear how surgery alters glucagon physiology. The aim of this study was to characterize the behavior of proglucagon-derived peptide (glucagon, glucagon-like peptide-1 (GLP-1), oxyntomodulin, glicentin) secretion after RYGB surgery.

Research design and methods

Prospective study of 19 patients with obesity and pre-diabetes/diabetes undergoing RYGB. We assessed the glucose, insulin, GLP-1, glucose-dependent insulinotropic peptide (GIP), oxyntomodulin, glicentin and glucagon responses to a mixed-meal test (MMT) before and 1, 3 and 12 months after surgery. Glucagon was measured using a Mercodia glucagon ELISA using the ‘Alternative’ improved specificity protocol, which was validated against a reference liquid chromatography combined with mass spectrometry method.

Results

After RYGB, there were early improvements in fasting glucose and glucose tolerance and the insulin response to MMT was accelerated and amplified, in parallel to significant increases in postprandial GLP-1, oxyntomodulin and glicentin secretion. There was a significant decrease in fasting glucagon levels at the later time points of 3 and 12 months after surgery. Glucagon was secreted in response to the MMT preoperatively and postoperatively in all patients and there was no significant change in this postprandial secretion. There was no significant change in GIP secretion.

Conclusions

There is a clear difference in the dynamics of secretion of proglucagon peptides after RYGB. The reduction in fasting glucagon secretion may be one of the mechanisms driving later improvements in glycemia after RYGB.

Trial registration number

NCT01945840.

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<![CDATA[Glucose metabolism among obese and non-obese children of mothers with gestational diabetes]]> https://www.researchpad.co/article/Nbc5cf79c-8d07-4fa0-a7c4-8c608bc5c43b

Objectives

Abdominal obesity is more closely associated with diabetes than general obesity in adults, however, it is unknown which kind of obesity is more closely associated with abnormal glucose metabolism in children.

Research design and methods

We recruited 973 children (aged 3.08±1.06) of mothers with prior gestational diabetes mellitus (GDM). Children’s height, weight, waist circumstance, fasting glucose and insulin were measured using standardized methods. Logistic regression models were used to assess the single and joint associations of general and abdominal obesity with the risks of hyperglycemia (the upper quartile of fasting glucose), insulin resistance (the upper quartile of homeostatic model assessment of insulin resistance (HOMA-IR)), and β-cell dysfunction (the lower quartile of HOMA-%β).

Results

Compared with normal weight children, children with general overweight/obesity had higher levels of HOMA-IR and HOMA-%β, higher ORs for hyperglycemia (1.56, 95% CI 1.06 to 2.30) and insulin resistance (3.44, 95% CI 2.32 to 5.09), but a lower OR for β-cell dysfunction (0.65, 95% CI 0.41 to 1.04). Children with abdominal obesity had an increased risk of insulin resistance (2.54, 95% CI 1.71 to 3.76) but not hyperglycemia and β-cell dysfunction compared with children with normal waist circumstance. In the joint analyses, general overweight children with and without abdominal obesity had an increased risk of hyperglycemia and insulin resistance compared with normal weight children.

Conclusions

General obesity was more closely associated with abnormal glucose metabolism than abdominal obesity in children of mothers with GDM.

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<![CDATA[Loss of voltage-gated proton channel Hv1 leads to diet-induced obesity in mice]]> https://www.researchpad.co/article/N5dc23c6e-94f2-4fc2-aad4-31232d1c5fe5

Objective

The voltage-gated proton channel Hv1 has been proposed to mediate NADPH oxidase (NOX) function by regulating intracellular pH during respiratory bursts. In our previous work, we showed that Hv1 is expressed in pancreatic β cells and positively regulates insulin secretion. Here, we investigated the role of Hv1 in adipose tissue differentiation, metabolic homeostasis and insulin sensitivity using Hv1 knockout (KO) mice.

Design

Mice with genetic deletion of Hv1 are treated with high-fat diet (HFD) similar to wild-type (WT) mice. Body weight gain, adiposity, insulin sensitivity and gene expressions in both adipose tissue and liver were analyzed.

Results

Mice with genetic deletion of Hv1 display overt obesity with higher body weight gain and accumulation of adipose tissue compared with similarly HFD-treated WT. Hv1-deficient mice develop more glucose intolerance than WT, but no significant difference in insulin resistance, after fed with HFD. Deficiency of Hv1 results in a remarkable increase in epididymal adipocyte weight and size, while the gene expressions of proinflammatory factors and cytokines are obviously enhanced in the HFD-fed mice. Furthermore, the gene expression of Hv1 is increased in the HFD-fed mice, which is accompanied by the increase of NOX2 and NOX4. In addition, there is more severely diet-induced steatosis and inflammation in liver in KO mice.

Conclusion

Our data demonstrated that lacking of Hv1 results in diet-induced obesity in mice through inflammation and hepatic steatosis. This study suggested that Hv1 acts as a positive regulator of metabolic homeostasis and a potential target for antiobesity drugs in therapy and may serve as an adaptive mechanism in cooperating with NOX to mediate reactive oxygen species for adipogenesis and insulin sensitivity.

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<![CDATA[Low-energy total diet replacement intervention in patients with type 2 diabetes mellitus and obesity treated with insulin: a randomized trial]]> https://www.researchpad.co/article/Ncff20266-a5ff-4287-b387-51d6cde913ea

Objectives

The management of patients with long-standing type 2 diabetes and obesity receiving insulin therapy (IT) is a substantial clinical challenge. Our objective was to examine the effect of a low-energy total diet replacement (TDR) intervention versus standardized dietetic care in patients with long-standing type 2 diabetes and obesity receiving IT.

Research design and methods

In a prospective randomized controlled trial, 90 participants with type 2 diabetes and obesity receiving IT were assigned to either a low-energy TDR (intervention) or standardized dietetic care (control) in an outpatient setting. The primary outcome was weight loss at 12 months with secondary outcomes including glycemic control, insulin burden and quality of life (QoL).

Results

Mean weight loss at 12 months was 9.8 kg (SD 4.9) in the intervention and 5.6 kg (SD 6.1) in the control group (adjusted mean difference −4.3 kg, 95% CI −6.3 to 2.3, p<0.001). IT was discontinued in 39.4% of the intervention group compared with 5.6% of the control group among completers. Insulin requirements fell by 47.3 units (SD 36.4) in the intervention compared with 33.3 units (SD 52.9) in the control (−18.6 units, 95% CI −29.2 to –7.9, p=0.001). Glycated Hemoglobin (HbA1c) fell significantly in the intervention group (4.7 mmol/mol; p=0.02). QoL improved in the intervention group of 11.1 points (SD 21.8) compared with 0.71 points (SD 19.4) in the control (8.6 points, 95% CI 2.0 to 15.2, p=0.01).

Conclusions

Patients with advanced type 2 diabetes and obesity receiving IT achieved greater weight loss using a TDR intervention while also reducing or stopping IT and improving glycemic control and QoL. The TDR approach is a safe treatment option in this challenging patient group but requires maintenance support for long-term success.

Trial registration number

ISRCTN21335883.

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<![CDATA[FGF21 Is a Hormonal Mediator of the Human “Thrifty” Metabolic Phenotype]]> https://www.researchpad.co/article/Nf5e4efd5-b517-4d29-b38b-1daee3c2ce2c

Fibroblast growth factor 21 (FGF21) regulates energy expenditure (EE) and influences weight change during low-protein overfeeding in rodent models. The change in EE after a low-protein overfeeding diet is a predictor of weight change in humans and a feature of the “thrifty” metabolic phenotype. However, there are no studies showing an association between circulating FGF21 and diet-related EE in humans. We assessed the changes in plasma FGF21 concentrations after 24 h of seven dietary interventions with different macronutrient content while in a whole-room indirect calorimeter in 64 healthy subjects with normal glucose regulation. Plasma FGF21 concentration consistently increased by threefold only after the two low-protein (3%) overfeeding diets, one high in carbohydrate (75%) and the other high in fat (46%), with larger increases in FGF21 being associated with greater increases in 24-h EE. Subjects with smaller increases in FGF21 after the low-protein high-fat diet gained more weight after 6 months in free-living conditions. Therefore, the individual predisposition to weight gain over time can be assessed by 24-h overfeeding a low-protein diet and measurements of plasma FGF21 concentrations. Individuals with a blunted FGF21 response to a low-protein diet have a thrifty metabolism and are at risk for future weight gain.

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<![CDATA[Sucrose Nonfermenting-Related Kinase Regulates Both Adipose Inflammation and Energy Homeostasis in Mice and Humans]]> https://www.researchpad.co/article/5c8eeb12d5eed0c484ef8eba

Sucrose nonfermenting-related kinase (SNRK) is a member of the AMPK-related kinase family, and its physiological role in adipose energy homeostasis and inflammation remains unknown. We previously reported that SNRK is ubiquitously and abundantly expressed in both white adipose tissue (WAT) and brown adipose tissue (BAT), but SNRK expression diminishes in adipose tissue in obesity. In this study we report novel experimental findings from both animal models and human genetics. SNRK is essential for survival; SNRK globally deficient pups die within 24 h after birth. Heterozygous mice are characterized by inflamed WAT and less BAT. Adipocyte-specific ablation of SNRK causes inflammation in WAT, ectopic lipid deposition in liver and muscle, and impaired adaptive thermogenesis in BAT. These metabolic disorders subsequently lead to decreased energy expenditure, higher body weight, and insulin resistance. We further confirm the significant association of common variants of the SNRK gene with obesity risk in humans. Through applying a phosphoproteomic approach, we identified eukaryotic elongation factor 1δ and histone deacetylase 1/2 as potential SNRK substrates. Taking these data together, we conclude that SNRK represses WAT inflammation and is essential to maintain BAT thermogenesis, making it a novel therapeutic target for treating obesity and associated metabolic disorders.

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<![CDATA[Longitudinal Analysis of Genetic Susceptibility and BMI Throughout Adult Life]]> https://www.researchpad.co/article/5c636818d5eed0c484b1b22a

Little is known about the genetic influence on BMI trajectory throughout adulthood. We created a genetic risk score (GRS) comprising 97 adult BMI-associated variants among 9,971 women and 6,405 men of European ancestry. Serial measures of BMI were assessed from 18 (women) or 21 (men) years to 85 years of age. We also examined BMI change in early (from 18 or 21 to 45 years of age), middle (from 45 to 65 years of age), and late adulthood (from 65 to 80 years of age). GRS was positively associated with BMI across all ages, with stronger associations in women than in men. The associations increased from early to middle adulthood, peaked at 45 years of age in men and at 60 years of age in women (0.91 and 1.35 kg/m2 per 10-allele increment, respectively) and subsequently declined in late adulthood. For women, each 10-allele increment in the GRS was associated with an average BMI gain of 0.54 kg/m2 in early adulthood, whereas no statistically significant association was found for BMI change in middle or late adulthood or for BMI change in any life period in men. Our findings indicate that genetic predisposition exerts a persistent effect on adiposity throughout adult life and increases early adulthood weight gain in women.

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<![CDATA[Objectively Measured Physical Activity, Sedentary Behavior, and Genetic Predisposition to Obesity in U.S. Hispanics/Latinos: Results From the Hispanic Community Health Study/Study of Latinos (HCHS/SOL)]]> https://www.researchpad.co/article/5c16375ed5eed0c48439d820

Studies using self-reported data suggest a gene–physical activity interaction on obesity, yet the influence of sedentary behavior, distinct from a lack of physical activity, on genetic associations with obesity remains unclear. We analyzed interactions of accelerometer-measured moderate to vigorous physical activity (MVPA) and time spent sedentary with genetic variants on obesity among 9,645 U.S. Hispanics/Latinos. An overall genetic risk score (GRS), a central nervous system (CNS)–related GRS, and a non-CNS-related GRS were calculated based on 97 BMI-associated single nucleotide polymorphisms (SNPs). Genetic association with BMI was stronger in individuals with lower MVPA (first tertile) versus higher MVPA (third tertile) (β = 0.78 kg/m2 [SE, 0.10 kg/m2] vs. 0.39 kg/m2 [0.09 kg/m2] per SD increment of GRS; Pinteraction = 0.005), and in those with more time spent sedentary (third tertile) versus less time spent sedentary (first tertile) (β = 0.73 kg/m2 [SE, 0.10 kg/m2] vs. 0.44 kg/m2 [0.09 kg/m2]; Pinteraction = 0.006). Similar significant interaction patterns were observed for obesity risk, body fat mass, fat percentage, fat mass index, and waist circumference, but not for fat-free mass. The CNS-related GRS, but not the non-CNS-related GRS, showed significant interactions with MVPA and sedentary behavior, with effects on BMI and other adiposity traits. Our data suggest that both increasing physical activity and reducing sedentary behavior may attenuate genetic associations with obesity, although the independence of these interaction effects needs to be investigated further.

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<![CDATA[Tbx15 Defines a Glycolytic Subpopulation and White Adipocyte Heterogeneity]]> https://www.researchpad.co/article/5c11bed1d5eed0c48477e596

Tbx15 is a member of the T-box gene family of mesodermal developmental genes. We have recently shown that Tbx15 plays a critical role in the formation and metabolic programming of glycolytic myofibers in skeletal muscle. Tbx15 is also differentially expressed among white adipose tissue (WAT) in different body depots. In the current study, using three independent methods, we show that even within a single WAT depot, high Tbx15 expression is restricted to a subset of preadipocytes and mature white adipocytes. Gene expression and metabolic profiling demonstrate that the Tbx15Hi preadipocyte and adipocyte subpopulations of cells are highly glycolytic, whereas Tbx15Low preadipocytes and adipocytes in the same depot are more oxidative and less glycolytic. Likewise, in humans, expression of TBX15 in subcutaneous and visceral WAT is positively correlated with markers of glycolytic metabolism and inversely correlated with obesity. Furthermore, overexpression of Tbx15 is sufficient to reduce oxidative and increase glycolytic metabolism in cultured adipocytes. Thus, Tbx15 differentially regulates oxidative and glycolytic metabolism within subpopulations of white adipocytes and preadipocytes. This leads to a functional heterogeneity of cellular metabolism within WAT that has potential impact in the understanding of human metabolic diseases.

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<![CDATA[Starch Digestion–Related Amylase Genetic Variant Affects 2-Year Changes in Adiposity in Response to Weight-Loss Diets: The POUNDS Lost Trial]]> https://www.researchpad.co/article/5c0d81f6d5eed0c484c06e42

Salivary and pancreatic amylases (encoded by AMY1 and AMY2 genes, respectively) are responsible for digesting starchy foods. AMY1 and AMY2 show copy number variations that affect differences in amylase amount and activity, and AMY1 copies have been associated with adiposity. We investigated whether genetic variants determining amylase gene copies are associated with 2-year changes in adiposity among 692 overweight and obese individuals who were randomly assigned to diets varying in macronutrient content. We found that changes in body weight (BW) and waist circumference (WC) were significantly different according to the AMY1-AMY2 rs11185098 genotype. Individuals carrying the A allele (indicating higher amylase amount and activity) showed a greater reduction in BW and WC at 6, 12, 18, and 24 months than those without the A allele (P < 0.05 for all). The association was stronger for long-term changes compared with short-term changes of these outcomes. The genetic effects on these outcomes did not significantly differ across diet groups. In conclusion, the genetic variant determining starch metabolism influences the response to weight-loss dietary intervention. Overweight and obese individuals carrying the AMY1-AMY2 rs11185098 genotype associated with higher amylase activity may have greater loss of adiposity during low-calorie diet interventions.

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<![CDATA[Alterations in 3-Hydroxyisobutyrate and FGF21 Metabolism Are Associated With Protein Ingestion–Induced Insulin Resistance]]> https://www.researchpad.co/article/5c047f21d5eed0c48472945b

Systemic hyperaminoacidemia, induced by either intravenous amino acid infusion or protein ingestion, reduces insulin-stimulated glucose disposal. Studies of mice suggest that the valine metabolite 3-hydroxyisobutyrate (3-HIB), fibroblast growth factor 21 (FGF21), adiponectin, and nonesterified fatty acids (NEFAs) may be involved in amino acid–mediated insulin resistance. We therefore measured in 30 women the rate of glucose disposal, and plasma 3-HIB, FGF21, adiponectin, and NEFA concentrations, under basal conditions and during a hyperinsulinemic-euglycemic clamp procedure (HECP), with and without concomitant ingestion of protein (n = 15) or an amount of leucine that matched the amount of protein (n = 15). We found that during the HECP without protein or leucine ingestion, the grand mean ± SEM plasma 3-HIB concentration decreased (from 35 ± 2 to 14 ± 1 µmol/L) and the grand median [quartiles] FGF21 concentration increased (from 178 [116, 217] to 509 [340, 648] pg/mL). Ingestion of protein, but not leucine, decreased insulin-stimulated glucose disposal (P < 0.05) and prevented both the HECP-mediated decrease in 3-HIB and increase in FGF21 concentration in plasma. Neither protein nor leucine ingestion altered plasma adiponectin or NEFA concentrations. These findings suggest that 3-HIB and FGF21 might be involved in protein-mediated insulin resistance in humans.

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<![CDATA[Id1 Promotes Obesity by Suppressing Brown Adipose Thermogenesis and White Adipose Browning]]> https://www.researchpad.co/article/5c01baadd5eed0c4841b8341

Obesity results from increased energy intake or defects in energy expenditure. Brown adipose tissue (BAT) is specialized for energy expenditure, a process called adaptive thermogenesis. Peroxisome proliferator–activated receptor γ coactivator 1α (PGC1α) controls BAT-mediated thermogenesis by regulating the expression of Ucp1. Inhibitor of differentiation 1 (Id1) is a helix-loop-helix transcription factor that plays an important role in cell proliferation and differentiation. We demonstrate a novel function of Id1 in BAT thermogenesis and programming of beige adipocytes in white adipose tissue (WAT). We found that adipose tissue–specific overexpression of Id1 causes age-associated and high-fat diet–induced obesity in mice. Id1 suppresses BAT thermogenesis by binding to and suppressing PGC1α transcriptional activity. In WAT, Id1 is mainly localized in the stromal vascular fraction, where the adipose progenitor/precursors reside. Lack of Id1 increases beige gene and Ucp1 expression in the WAT in response to cold exposure. Furthermore, brown-like differentiation is increased in Id1-deficient mouse embryonic fibroblasts. At the molecular level, Id1 directly interacts with and suppresses Ebf2 transcriptional activity, leading to reduced expression of Prdm16, which determines beige/brown adipocyte cell fate. Overall, the study highlights the existence of novel regulatory mechanisms between Id1/PGC1α and Id1/Ebf2 in controlling brown fat metabolism, which has significant implications in the treatment of obesity and its associated diseases, such as diabetes.

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<![CDATA[Effects of Aerobic Versus Resistance Exercise Without Caloric Restriction on Abdominal Fat, Intrahepatic Lipid, and Insulin Sensitivity in Obese Adolescent Boys]]> https://www.researchpad.co/article/5b9fbd3240307c778d139343

The optimal exercise modality for reductions of abdominal obesity and risk factors for type 2 diabetes in youth is unknown. We examined the effects of aerobic exercise (AE) versus resistance exercise (RE) without caloric restriction on abdominal adiposity, ectopic fat, and insulin sensitivity and secretion in youth. Forty-five obese adolescent boys were randomly assigned to one of three 3-month interventions: AE, RE, or a nonexercising control. Abdominal fat was assessed by magnetic resonance imaging, and intrahepatic lipid and intramyocellular lipid were assessed by proton magnetic resonance spectroscopy. Insulin sensitivity and secretion were evaluated by a 3-h hyperinsulinemic-euglycemic clamp and a 2-h hyperglycemic clamp. Both AE and RE prevented the significant weight gain that was observed in controls. Compared with controls, significant reductions in total and visceral fat and intrahepatic lipid were observed in both exercise groups. Compared with controls, a significant improvement in insulin sensitivity (27%) was observed in the RE group. Collapsed across groups, changes in visceral fat were associated with changes in intrahepatic lipid (r = 0.72) and insulin sensitivity (r = −0.47). Both AE and RE alone are effective for reducing abdominal fat and intrahepatic lipid in obese adolescent boys. RE but not AE is also associated with significant improvements in insulin sensitivity.

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<![CDATA[Increased Expression of Macrophage-Inducible C-type Lectin in Adipose Tissue of Obese Mice and Humans]]> https://www.researchpad.co/article/5ac1e0e3463d7e4ad7e96898

OBJECTIVE

We have provided evidence that saturated fatty acids, which are released from adipocytes via macrophage-induced adipocyte lipolysis, serve as a naturally occurring ligand for the Toll-like receptor (TLR) 4 complex in macrophages, thereby aggravating obesity-induced adipose tissue inflammation. The aim of this study was to identify the molecule(s) activated in adipose tissue macrophages in obesity.

RESEARCH DESIGN AND METHODS

We performed a cDNA microarray analysis of coculture of 3T3-L1 adipocytes and RAW264 macrophages. Cultured adipocytes and macrophages and the adipose tissue of obese mice and humans were used to examine mRNA and protein expression.

RESULTS

We found that macrophage-inducible C-type lectin (Mincle; also called Clec4e and Clecsf9), a type II transmembrane C-type lectin, is induced selectively in macrophages during the interaction between adipocytes and macrophages. Treatment with palmitate, a major saturated fatty acid released from 3T3-L1 adipocytes, induced Mincle mRNA expression in macrophages at least partly through the TLR4/nuclear factor (NF)-κB pathway. Mincle mRNA expression was increased in parallel with macrophage markers in the adipose tissue of obese mice and humans. The obesity-induced increase in Mincle mRNA expression was markedly attenuated in C3H/HeJ mice with defective TLR4 signaling relative to control C3H/HeN mice. Notably, Mincle mRNA was expressed in bone-marrow cell (BMC)-derived proinflammatory M1 macrophages rather than in BMC-derived anti-inflammatory M2 macrophages in vitro.

CONCLUSIONS

Our data suggest that Mincle is induced in adipose tissue macrophages in obesity at least partly through the saturated fatty acid/TLR4/NF-κB pathway, thereby suggesting its pathophysiologic role in obesity-induced adipose tissue inflammation.

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<![CDATA[Distinct Networks of Leptin- and Insulin-Sensing Neurons Regulate Thermogenic Responses to Nutritional and Cold Challenges]]> https://www.researchpad.co/article/5bc5c46c40307c51dd5ac98b

Defense of core body temperature (Tc) can be energetically costly; thus, it is critical that thermoregulatory circuits are modulated by signals of energy availability. Hypothalamic leptin and insulin signals relay information about energy status and are reported to promote thermogenesis, raising the possibility that they interact to direct an appropriate response to nutritional and thermal challenges. To test this idea, we used an Nkx2.1-Cre driver to generate conditional knockouts (KOs) in mice of leptin receptor (L2.1KO), insulin receptor (I2.1KO), and double KOs of both receptors (D2.1KO). L2.1KOs are hyperphagic and obese, whereas I2.1KOs are similar to controls. D2.1KOs exhibit higher body weight and adiposity than L2.1KOs, solely due to reduced energy expenditure. At 20–22°C, fed L2.1KOs maintain a lower baseline Tc than controls, which is further decreased in D2.1KOs. After an overnight fast, some L2.1KOs dramatically suppress energy expenditure and enter a torpor-like state; this behavior is markedly enhanced in D2.1KOs. When fasted mice are exposed to 4°C, L2.1KOs and D2.1KOs both mount a robust thermogenic response and rapidly increase Tc. These observations support the idea that neuronal populations that integrate information about energy stores to regulate the defense of Tc set points are distinct from those required to respond to a cold challenge.

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<![CDATA[Obesity-Associated Hepatosteatosis and Impairment of Glucose Homeostasis Are Attenuated by Haptoglobin Deficiency]]> https://www.researchpad.co/article/5ac619b5463d7e2c1af8ab09

OBJECTIVE

Haptoglobin (Hp) is upregulated in both inflammation and obesity. The low chronic inflammatory state, caused by massive adipose tissue macrophage (ATM) infiltration found in obesity, and low adiponectin have been implicated in the development of insulin resistance and hepatosteatosis. The aim of this work was to investigate whether and how Hp interferes with the onset of obesity-associated complications.

RESEARCH DESIGN AND METHODS

Hp-null (Hp−/−) and wild-type (WT) mice were metabolically profiled under chow-food diet (CFD) and high-fat diet (HFD) feeding by assessing physical parameters, glucose tolerance, insulin sensitivity, insulin response to glucose load, liver triglyceride content, plasma levels of leptin, insulin, glucose, and adiponectin. ATM content was evaluated by using immunohistochemistry (anti-F4/80 antibody). Adiponectin expression was measured in Hp-treated, cultured 3T3-L1 and human adipocytes.

RESULTS

No genotype-related difference was found in CFD animals. HFD-Hp−/− mice revealed significantly higher glucose tolerance, insulin sensitivity, glucose-stimulated insulin secretion, and adiponectin expression and reduced hepatomegaly/steatosis compared with HFD-WT mice. White adipose tissue (WAT) of HFD-Hp−/− mice showed higher activation of insulin signaling cascade, lower ATM, and higher adiponectin expression. Hp was able to inhibit adiponectin expression in cultured adipocytes.

CONCLUSIONS

We demonstrated that in the absence of Hp, obesity-associated insulin resistance and hepatosteatosis are attenuated, which is associated with reduced ATM content, increased plasma adiponectin, and higher WAT insulin sensitivity.

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<![CDATA[Depressed Levels of Prostaglandin F2α in Mice Lacking Akr1b7 Increase Basal Adiposity and Predispose to Diet-Induced Obesity]]> https://www.researchpad.co/article/5b9fbd2840307c778d13933e

Negative regulators of white adipose tissue (WAT) expansion are poorly documented in vivo. Prostaglandin F (PGF) is a potent antiadipogenic factor in cultured preadipocytes, but evidence for its involvement in physiological context is lacking. We previously reported that Akr1b7, an aldo-keto reductase enriched in adipose stromal vascular fraction but absent from mature adipocytes, has antiadipogenic properties possibly supported by PGF synthase activity. To test whether lack of Akr1b7 could influence WAT homeostasis in vivo, we generated Akr1b7−/− mice in 129/Sv background. Akr1b7−/− mice displayed excessive basal adiposity resulting from adipocyte hyperplasia/hypertrophy and exhibited greater sensitivity to diet-induced obesity. Following adipose enlargement and irrespective of the diet, they developed liver steatosis and progressive insulin resistance. Akr1b7 loss was associated with decreased PGF WAT contents. Cloprostenol (PGF agonist) administration to Akr1b7−/− mice normalized WAT expansion by affecting both de novo adipocyte differentiation and size. Treatment of 3T3-L1 adipocytes and Akr1b7−/− mice with cloprostenol suggested that decreased adipocyte size resulted from inhibition of lipogenic gene expression. Hence, Akr1b7 is a major regulator of WAT development through at least two PGF-dependent mechanisms: inhibition of adipogenesis and lipogenesis. These findings provide molecular rationale to explore the status of aldo-keto reductases in dysregulations of adipose tissue homeostasis.

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<![CDATA[Macrophage Proliferation Sustains Adipose Tissue Inflammation in Formerly Obese Mice]]> https://www.researchpad.co/article/5bf4e3d0d5eed0c484804572

Obesity causes dramatic proinflammatory changes in the adipose tissue immune environment, but relatively little is known regarding how this inflammation responds to weight loss (WL). To understand the mechanisms by which meta-inflammation resolves during WL, we examined adipose tissue leukocytes in mice after withdrawal of a high-fat diet. After 8 weeks of WL, mice achieved similar weights and glucose tolerance values as age-matched lean controls but showed abnormal insulin tolerance. Despite fat mass normalization, total and CD11c+ adipose tissue macrophage (ATM) content remained elevated in WL mice for up to 6 months and was associated with persistent fibrosis in adipose tissue. ATMs in formerly obese mice demonstrated a proinflammatory profile, including elevated expression of interferon-γ, tumor necrosis factor-α, and interleukin-1β. T-cell–deficient Rag1−/− mice showed a degree of ATM persistence similar to that in WT mice, but with reduced inflammatory gene expression. ATM proliferation was identified as the predominant mechanism by which ATMs are retained in adipose tissue with WL. Our study suggests that WL does not completely resolve obesity-induced ATM activation, which may contribute to the persistent adipose tissue damage and reduced insulin sensitivity observed in formerly obese mice.

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