Diabetes & Metabolism Journal

Review

Basic Research
Brown Fat as a Regulator of Systemic Metabolism beyond Thermogenesis: Okamatsu-Ogura Yuko, Masayuki Saito; Diabetes Metab J. 2021;45(6):840-852. Published online June 25, 2021; DOI: https://doi.org/10.4093/dmj.2020.0291

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Brown adipose tissue (BAT) is a specialized tissue for nonshivering thermogenesis to dissipate energy as heat. Although BAT research has long been limited mostly in small rodents, the rediscovery of metabolically active BAT in adult humans has dramatically promoted the translational studies on BAT in health and diseases. Moreover, several remarkable advancements have been made in brown fat biology over the past decade: The molecular and functional analyses of inducible thermogenic adipocytes (socalled beige adipocytes) arising from a developmentally different lineage from classical brown adipocytes have been accelerated. In addition to a well-established thermogenic activity of uncoupling protein 1 (UCP1), several alternative thermogenic mechanisms have been discovered, particularly in beige adipocytes. It has become clear that BAT influences other peripheral tissues and controls their functions and systemic homeostasis of energy and metabolic substrates, suggesting BAT as a metabolic regulator, other than for thermogenesis. This notion is supported by discovering that various paracrine and endocrine factors are secreted from BAT. We review the current understanding of BAT pathophysiology, particularly focusing on its role as a metabolic regulator in small rodents and also in humans.

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Original Articles

Association between Type 2 Diabetes and Genetic Variations in Uncoupling Protein 2, beta3-Adrenergic Receptor, and Peroxisome Proliferator-Activated Receptor gamma in Korean.: Min Kyong Moon, Young Min Cho, Hye Seung Jung, Tae Yong Kim, Yun Yong Lee, Joong Yeol Park, Ki Up Lee, Chan Soo Shin, Kyong Soo Park, Seong Yeon Kim, Hong Kyu Lee, Hyoung Doo Shin; Korean Diabetes J. 2002;26(6):469-480. Published online December 1, 2002

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Abstract PDF: BACKGROUND
Type 2 diabetes mellitus is a multifactorial disease influenced by numerous genetic and environmental factors. The uncoupling proteins, 2 (UCP2), beta3-adrenergic receptor ADRB3, and peroxisome proliferator-activated receptor gamma PPAR gamma, are genes involved in energy expenditure and fatty acid metabolisms, ans are therefore regarded as candidate genes for type 2 diabetes. In this study, we examined whether the known polymorphisms of UCP2, ADRB3 and PPAR gamma are associated with type 2 diabetes in the Korean population. METHODS: We studied 516 type 2 diabetic patients and 147 control subjects. The enrollment criteria for the control subjects were as follows; age > 60 years, no family history of diabetes in their first-degree relatives, a fasting plasma glucose (FPG) < 6.1 mmol/L, and a HbA1C < 5.8%. Height, weight, waist and hip circumference, FPG, 2 hour-plasma glucose after 75g-glucose load (2h-PG), blood pressure, lipid profile, and fasting insulin level were measured. The Ala55Val polymorphism of the UCP2, Trp64Arg polymorphism of the ADRB3, and Pro12Ala polymorphism of the PPAR gamma were determined by single base extension method. RESULTS: The allele frequency of the Ala55Val variant of the UCP2 tended to be higher in the control subjects than in the type 2 diabetic patients (0.497 vs. 0.456, p=0.064). The allele frequencies of the Trp64Arg polymorphism of the ADRB3, and the Pro12Ala polymorphism of the PPAR gamma, were comparable between the diabetic patients and the control subjects (0.141 vs. 0.152 and 0.033 vs. 0.041, respectively). In the control subjects, the Ala55Val polymorphism of the UCP2 was associated with a significantly lower 2h-PG compared to the wild type (6.0 +/- 0.8 mmol/L vs. 6.6 +/- 0.7 mmol/L, p=0.002). The female control subjects, with the ADRB3 Trp64Arg variant, had a significantly lower triglyceride level than those without the variant (1.36 +/- 0.53 mmol/L vs. 1.74 +/- 0.82 mmol/L, p=0.020). The type 2 diabetic patients, with the ADRB3 Trp64Arg variant showed a significantly lower body mass index (23.6 +/- 2.6 kg/m2vs. 24.6 +/- 3.0 kg/m2, p=0.001). The PPAR gamma Pro12Ala variant, was not associated with any of the features of insulin resistance. The combined genotype of the Val allele of UCP2, Trp allele of ADRB3 and Ala allele of PPAR gamma was less frequent among the type 2 diabetes patients than the control subjects (0.020 vs. 0.056, p=0.039). CONCLUSION: The Ala55Val variant of the UCP2, the Trp64Arg variant of the ADRB3 and the Pro12Ala variant of the PPAR gamma, were not associated with type 2 diabetes in the Korean population. However, the Ala55Val variant of the UCP2 was associated with a lower 2h-PG in the control subjects and the Trp64Arg variant of the ADRB3 was associated with a lower triglyceride level in the female control subjects. Further study may be required to elucidate if the combined genotype of Val allele of UCP2, Trp allele of ADRB3 and Ala allele of PPAR gamma would be protective against type 2 diabetes.

Anti-obesity Effects of alpha-lipoic Acid in OLETF Rats.: Kee Ho Song, Ji Young Youn, Chul Nam Koong, Min Jeong Shin, Jae Won Ryu, Hye Sun Park, Min Seon Kim, Joong Youl Park, Ki Up Lee; Korean Diabetes J. 2002;26(6):460-468. Published online December 1, 2002

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Abstract PDF: BACKGROUND
Obesity is closely related to the development of type 2 diabetes mellitus, hypertension and cardiovascular disease. While the prevalence of obesity is rapidly increasing in most parts of the world, its effective treatment is not available due to the limited efficacy, and the side effects, of anti-obesity drugs. We unexpectedly found that administration of alpha-lipoic acid (ALA) resulted in a significant reduction in the body weight of rodents. This study aimed to investigate the mechanisms of the anti-obesity effect of ALA in the obese diabetic models of Otsuka Long Evans Tokushima (OLETF) rats. MATERIALS AND METHODS: Ten weeks old male OLETF rats were randomly assigned into one of three groups (n=6 per group): 1) the control group, fed with normal rat chow 2) the ALA group, fed with rat chow containing ALA (0.5% of food weight) and 3) the pair-fed group, fed with normal rat chow, but given the same amount of food as consumed by the ALA group. The body weight and food intakes were monitored for 3 weeks. At the end of the study, abdominal CT scans were performed to measure the visceral fat content. The energy expenditure and respiratory quotient were measured on days 3, 9 and 21 using an indirect calorimeter. The expression of the uncoupling protein-1 mRNA in the white and brown adipose tissues were determined by Northern blot analyses. The oxidation of fatty acids in the skeletal muscle, liver and adipose tissue was also measured. RESULTS: The administration of ALA induced a significant weight loss and reduction in food intake throughout the study period. The weight loss in the ALA group was greater than in the pair-fed group (p<0.05), suggesting an enhanced energy metabolism in the ALA group. In the ALA treated animals, the energy expenditure was significantly increased together with an elevated expression of UCP-1 mRNA in the brown, and an ectopic expression of UCP-1 mRNA in the white adipose tissues. The oxidation of fat in the brown adipose tissue and skeletal muscle was also increased after the ALA treatment, which was in line with the reduced respiratory quotient in the ALA group. The abdominal CT scan revealed a reduction in the visceral fat content in the ALA group compared to the control group. CONCLUSION: The present study demonstrated, for the first time, a novel anti-obesity action of ALA in obese OLETF rats, which proceeds through at least three different mechanisms: 1) reduction in food intake, 2) increase in energy expenditure and 3) enhancement of fat oxidation.

Polymorphism of the Uncoupling Protein 1 (UCP-1) Gene and Fatty Acid Binding Protein 2 (FABP2) Gene in Korean Type 2 Diabetic Patients.: Sun Gyu Kim, Chul Hee Kim, Seog Ki Yun, Yeo Il Yun, Yong Hyun Kim, Il Song Nam, Ju Young Lee, Ji O Mok, Hyeong Kyu Park, Young Sun Kim, Dong Won Byun, Kyo Il Suh, Myung Hi Yoo; Korean Diabetes J. 2001;25(4):262-272. Published online August 1, 2001

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Abstract PDF: BACKGROUND
It is well known that genetic component plays an important role in developing obesity and type 2 diabetes mellitus. A number of candidate genes have been suggested, but the major gene determining the development of obesity and type 2 diabetes has not yet been uncovered. Previous studies suggest that polymorphisms of the intestinal fatty acid binding protein (FABP2) and uncoupling protein 1 (UCP-1) gene were related with obesity and/or insulin resistance in several populations. METHODS: We examined 76 type 2 diabetic patients (aged 44+/-6 years) and 96 healthy controls (aged 25+/-3 years). Ala54Thr polymorphism of the FABP2 gene and A to G polymorphism (-3826) of the UCP-1 gene were determined by polymerase chain reaction and restriction fragment length polymorphism method. RESULTS: The Thr54 allele of the FABP2 gene was found with a frequency of 0.33 in nondiabetic controls and 0.36 in type 2 diabetic patients. The genotype frequency of the Ala54Thr polymorphism was similar in nondiabetic and diabetic subjects ( 2=0.87, P=0.64). The -3826 G allele of UCP-1 gene was found with a frequency of 0.51 in nondiabetic controls, and 0.46 in type 2 diabetic patients. The genotype frequency of the -3826 A to G polymorphism was also similar in nondiabetic and diabetic subjects ( 2=1.46, p=0.46). When the subjects of each groups were subdivided into nonobese and obese group by BMI of 25 kg/m2, there was no significant difference in genotype frequencies of the UCP-1 and FABP2 gene polymorphisms. CONCLUSION: These results suggest that either the Ala54Thr polymorphism of the FABP2 gene or the A to G polymorphism (-3826) of UCP-1 gene do not play a major role in developing type 2 diabetes mellitus or obesity in Korean.

Association Between Uncoupling Protein-1 and 3-adrenergic Receptor Gene Polymorphisms and Energy Metabolism in normal Korean Adults.: Jae Han Kim, Seog Ki Yun, Chul Hee Kim, Dong Won Byun, Young Sun Kim, Kyo Il Suh, Myung Hi Yoo; Korean Diabetes J. 1999;23(6):803-813. Published online January 1, 2001

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Abstract PDF: BACKGROUND
The beta3-adrenergic receptor (beta3-AR) and uncoupling protein 1 (UCP-1), expressed mainly in brown adipose tissue, are involved in the regulation of thermogenesis and lipolysis. Recent studies have shown that polymorphisms of the 3-AR (Trp64Arg) and UCP-1 (-3826, A to G) genes are associated with low basal metabolic rate (BMR) and obesity. METHODS: We investigated the effects of the beta3- AR and UCP-1 gene polymorphisms on body fat and energy metabolism in 65 normal Korean men aged from 21 to 36 years. The Trp64Arg mutation of the beta3-AR gene and A to G polymorphism (-3826) of UCP-1 gene were detected by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) method. RESULT: In normal Koreans, Arg64 allele frequency of the beta3-AR was 0.15 and the allele frequency of the A to G substitution of the UCP-1 gene was 0.48. No significant difference was found in BMR, body fat and abdominal fat amount in relation to beta3-AR or UCP-1 genotypes. However, when the polymorphisms of the two genes were combined, the subjects with the polymorphisms of both UCP-1 and g-AR genes were found to have higher body mass index, higher total fat and abdominal fat amount, lower BMR, and lower fat oxidation rate when compared with the subjects without these polymorphisms. CONCLUSION: These results suggest that the polymorphisms of either beta3-AR or UCP-1 gene alone did not significantly affect BMR, fat oxidation and body fat amounts, but both UCP-1 and beta3-AR genes polymorphisms have synergistic effects on decreased basal metabolic rate, fat oxidation rate, and increased body fat in normal Korean adults.

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