Activating Connexin43 gap junctions primes adipose tissue for therapeutic intervention

Adipose tissue is a promising target for treating obesity and metabolic diseases. However, pharmacological agents usually fail to effectively engage adipocytes due to their extraordinarily large size and insufficient vascularization, especially in obese subjects. We have previously shown that during cold exposure, connexin43 (Cx43) gap junctions are induced and activated to connect neighboring adipocytes to share limited sympathetic neuronal input amongst multiple cells. We reason the same mechanism may be leveraged to improve the efficacy of various pharmacological agents that target adipose tissue. Using an adipose tissue-specific Cx43 overexpression mouse model, we demonstrate effectiveness in connecting adipocytes to augment metabolic efficacy of the β 3-adrenergic receptor agonist Mirabegron and FGF21. Additionally, combing those molecules with the Cx43 gap junction channel activator danegaptide shows a similar enhanced efficacy. In light of these findings, we propose a model in which connecting adipocytes via Cx43 gap junction channels primes adipose tissue to pharmacological agents designed to engage it. Thus, Cx43 gap junction activators hold great potential for combination with additional agents targeting adipose tissue.

Association Between Trp64arg Polymorphism of the β3 adrenoreceptor Gene and Female Sex in Obese Turkish Children and Adolescents / 대한소아소화기영양학회지

PURPOSE: The β3-adrenergic receptor (ADRB3) is expressed in visceral adipose tissue and has been speculated to contribute to lipolysis, energy metabolism, and regulation of the metabolic rate. In this study, we aimed to investigate the association of polymorphism of the ADRB3 gene with the sex of children with obesity and related pathologies. METHODS: ADRB3 gene trp64arg genotyping was conducted in 441 children aged 6–18 years. Among these subjects, 264 were obese (103 boys; 161 girls) and 179 were of normal weight (81 boys; 98 girls). In the obese group, fasting lipids, glucose and insulin levels, and blood pressure were measured. Metabolic syndrome (MS) was defined according to the modified World Health Organization criteria adapted for children. RESULTS: The frequency of trp64arg genotype was similar in obese and normal weight children. In obese children, serum lipid, glucose, and insulin levels; homeostasis model assessment of insulin resistance (HOMA-IR) scores; and MS were not different between arg allele carriers (trp64arg) and noncarriers (trp64trp). In 264 obese children, genetic analysis results revealed that the arg allele carriers were significantly higher in girls than in boys (p=0.001). In the normal weight group, no statistically significant difference was found between genotypes of boys and girls (p=0.771). CONCLUSION: Trp64arg polymorphism of the ADRB3 gene was not associated with obesity and MS in Turkish children and adolescents. Although no relationships were observed between the genotypes and lipids, glucose/insulin levels, or HOMA-IR, the presence of trp64arg variant was frequent in obese girls, which can lead to weight gain as well as difficulty in losing weight in women.

Association of polymorphism of β3-adrenergic receptor gene and the leptin gene with Kazak obese children in Xinjiang / 中华实用儿科临床杂志

Objective To investigate the association between C2549A polymorphism of leptin gene and the Trp64Arg polymorphism of the β3-adrenergic receptor gene(β3-AR gene) and obesity in Kazak school-age children.Methods Totally 92 obese children and 71 healthy controls were selected from 6 to 12 years old in Kazak school-age children from the area around Urumqi.Genotype of the C2549A polymorphism of leptin gene and the Trp64Arg polymor phism of β3-AR gene were determined by polymerase chain reaction and restriction fragment length polymorphism methods.Results 1.The difference in distribution of the β3-AR gene Trp64Arg genotype of obesity and healthy controls of Kazak children was statistically significant (x2 =10.472,P ＜ 0.05),but the difference in distribution of the alleles was not statistically significant (x2 =3.541,P ＞ 0.05).2.The differences in distribution of the leptin C2549A genotype and alleles of the 2 groups were all statistically significant,and the odds ratio of the alleles(0.608) and 95％ CI 0.380-0.972 suggested that the mutation occurrence of obesity might have certain protective effect.3.The difference in distribution of the genotype of β3-AR gene Trp64Arg polymorphism and leptin gene promoter area C2549A polymorphism in the same individual joint action of 2 groups was statistically significant (x2 =15.978,P ＜ 0.05),but the difference in distribution of the alleles in the same individual joint action of 2 groups was not statistically significant (x2 =6.362,P ＞ 0.05).Conclusions 1.There were distributions of the Trp64Arg polymorphism of β3-AR gene and the C2549A polymorphism of leptin gene in Kazak school-aged children in Xinjiang.2.These results suggested that C2549A mutation of leptin gene might have certain protective effect in Kazak children obesity,and the Trp64Arg polymorphism of β3-AR gene might be associated with Kazak children obesity.3.These results suggested that the Trp64Arg polymorphism of β3-AR gene and the C2549A polymorphism of leptin gene in the same individual joint action might be associated with Kazak children obesity in Xinjiang.

Effect of BRL37344 on cardiac fibroblast phosphatidylinositol 3-kinase-protein kinase B signal transduction pathway / 中华急诊医学杂志

Objective To explore the effects of the β3 adrenergic receptor (β3-AR) agonist BRL37344 on cardiac fibroblast proliferation and collagen fiber hyperplasia in Wistar rats by promoting the phosphaticlylinositol 3 kinase-protein kinase B(PI3K-Akt) signal transduction pathway. Method Cardiac fibroblasts(CFbs) were isolated from 1 - 3 day-old Wistar rats under the sterile environment in the laboratory of the First Affiliated Hospital of Hasbin Medical University, by using enzyme digestion and an modified technique of differential anchoring velocity.The cultured myocardial cells were randomly (random number) divided into five groups. ① In blank group, rats were not treated with drug; ②in BRL group, rats were treated with BRL37344; ③in LY group, rats were treated with LY294002(PI3K antagonist) for one hour before treated with BRL37344;④in Akt-Ⅰ group,rats were treated with Akt-Ⅰ (Akt antagonist) for one hour before treated with BRL37344;⑤in L-A group, rats were treated with LY294002 and Akt-Ⅰ for one hour before treated with BRL37344. MTT colorimetric method and RT-PCR were used to observe the role of β3-AR agonist with or without PI3K antagonist and/or Akt antagonist in cardiac fibroblast proliferation (CFP) and collagen fiber hyperplasia (CFH). Comparisons between groups were made by one-way ANOVA and Tukey test. Results ①β3-AR was present in the CFbs. ②Compared with BRL group, the CFP and CFH in LY and Akt-Ⅰ groups were lower (P ＜0.01) and those in L-A group were lowest (P ＜ 0.01). ③Compared with blank group,the expressions of type Ⅰ and type Ⅲ fiber mRNA obliviously increased in BRL group (P ＜ 0.01),and at 48 hours,the expressionrs reached peak. At 48 hours,compared with BRL group,the expressions in LY and Akt-Ⅰ groups were lower, and were lowest in L-A group ( P ＜0.01). Conclusions BRL37344 promotes cardiac fibroblast proliferation and expressions of type Ⅰ and Ⅲ collagen fiber mRNA by activating the PI3K-Akt signal transduction pathway.

Effect of β(3)-adrenergic receptor gene polymorphism on body weight change in middle-aged, overweight women

<p><b>OBJECTIVES</b>To examine the effects of β(3)-adrenergic receptor gene polymorphism on body weight change during a weight reduction program for middle-aged, overweight women with careful consideration of their energy intake and expenditure.</p><p><b></b>METHODS</p><p><b>DESIGN</b>Intervention study of weight reduction for 12 weeks in a community setting.</p><p><b>SUBJECTS</b>Eighty overweight middle-aged women who completed the individualized lifestyle modification program.</p><p><b>MEASUREMENTS</b>β(3)-adrenergic receptor gene polymorphism was identified by polymerase chain reaction and consecutive restriction fragment-length polymorphism analysis. Anthropometrical parameters, lifestyle factors, blood lipid and glucose levels, physical activity level and energy intake were measured before and at the end of the program.</p><p><b>RESULTS</b>The numbers of subjects with the Trp64Trp, Trp64Arg, and Arg64Arg genotypes were 45, 30 and 5, respectively. Baseline characteristics among subjects with the 64Arg allele had significantly smaller decrease in body weight and energy intake than those without the 64Arg allele. The change of other clinical characteristics did not differ between the two groups. After adjusting for the %change of energy intake, the %change of body weight did not differ between the two groups.</p><p><b>CONCLUSION</b>The 64Arg allele of the β(3)-AR gene is not likely to be the factor determining the difficulty in losing body weight in Japanese middle-aged, overweight women. Lifestyle factors, such as the decrease in energy intake, might mask the effect of the 64Arg allele on body weight loss. Specific considerations for the management of energy intake would be needed to promote body weight loss for those with the 64Arg allele.</p>

Effect of $\beta$_{3}-Adrenergic Receptor Gene Polymorphism on Body Weight Change in Middle-Aged, Overweight Women

Objectives: To examine the effects of β3-adrenergic receptor gene polymorphism on body weight change during a weight reduction program for middle-aged, overweight women with careful consideration of their energy intake and expenditure. Methods: Design: Intervention study of weight reduction for 12 weeks in a community setting. Subjects: Eighty overweight middle-aged women who completed the individualized lifestyle modification program. Measurements: β3-adrenergic receptor gene polymorphism was identified by polymerase chain reaction and consecutive restriction fragment-length polymorphism analysis. Anthropometrical parameters, lifestyle factors, blood lipid and glucose levels, physical activity level and energy intake were measured before and at the end of the program. Results: The numbers of subjects with the Trp64Trp, Trp64Arg, and Arg64Arg genotypes were 45, 30 and 5, respectively. Baseline characteristics among subjects with the Trp64Trp, Trp64Arg and Arg64Arg alleles did not differ. After 12 weeks, the subjects with the 64Arg allele had significantly smaller decrease in body weight and energy intake than those without the 64Arg allele. The change of other clinical characteristics did not differ between the two groups. After adjusting for the %change of energy intake, the %change of body weight did not differ between the two groups. Conclusion: The 64Arg allele of the β3-AR gene is not likely to be the factor determining the difficulty in losing body weight in Japanese middle-aged, overweight women. Lifestyle factors, such as the decrease in energy intake, might mask the effect of the 64Arg allele on body weight loss. Specific considerations for the management of energy intake would be needed to promote body weight loss for those with the 64Arg allele.