11/08/2013

White adipose tissue (WAT) stores fat and secrets adipokines in the control of energy balance. With the two functions, WAT regulates energy expenditure through lipolysis and leptin. Those are the indirect effects of WAT in the control of energy balance. However, recent studies reveal a direct effect of WAT. This effect is mediated by a group of WAT cells named “beige/brite”, which are not brown adipocytes but able to produce heat like brown adipocytes. An increase in beige/brite cells is called WAT browning. In transgenic mice, WAT browning is able to reduce risk for obesity and insulin resistance through releasing energy in heat. The browning is a new concept in the control of obesity and type 2 diabetes. There are about 50 genes known to increase browning as summarized in two recent reviews (1; 2). There is new technology to track the source of beige/brite cells in WAT in Nature Medicine (3).

Reference
1. Harms M, Seale P: Brown and beige fat: development, function and therapeutic potential. Nat Med 2013;19:1252-1263
2. Wu J, Cohen P, Spiegelman BM: Adaptive thermogenesis in adipocytes: is beige the new brown? Genes Dev 2013;27:234-250
3. Wang QA, Tao C, Gupta RK, Scherer PE: Tracking adipogenesis during white adipose tissue development, expansion and regeneration. Nat Med 2013;19:1338-1344

9/20/2013

In a recent mouse study (1), omega-3 fatty acids is reported to prevent inflammation and metabolic disorder through inhibition of NLRP3 inflammasome activation. Together with a report early this year (2), the study provides new support to the existing concept that inflammation is a target in the improvement of insulin sensitivity for type 2 diabetes. Although there is strong rodent evidence, the human evidence remains missing for the concept. In an excellent human study (3), the anti-inflammatory medicine salsalate improved glucose, but not insulin sensitivity in the type 2 diabetic patients. A reduction in HbA1c is associated with an elevation in blood insulin and body weight in the patients. This human study might be the only accomplished large clinical trial. Two large trials for anti-IL-1 had been terminated before completion. The physiological difference between mouse and human is one possibility for the discrepancy in response to the anti-inflammation treatments. Another difference is that “mouse cannot speak English”, which is well known in the cancer therapy. The third possibility is that the inflammation concept is over simplified due to missing the beneficial effects of metabolic inflammation in vivo (4). Have a nice weekend!

Reference
1. Yan Y, Jiang W, Spinetti T, Tardivel A, Castillo R, Bourquin C, Guarda G, Tian Z, Tschopp J, Zhou R: Omega-3 fatty acids prevent inflammation and metabolic disorder through inhibition of NLRP3 inflammasome activation. Immunity 2013;38:1154-1163
2. Reilly SM, Chiang S-H, Decker SJ, Chang L, Uhm M, Larsen MJ, Rubin JR, Mowers J, White NM, Hochberg I, Downes M, Yu RT, Liddle C, Evans RM, Oh D, Li P, Olefsky JM, Saltiel AR: An inhibitor of the protein kinases TBK1 and IKK-[epsiv] improves obesity-related metabolic dysfunctions in mice. Nat Med 2013;19:313-321
3. Goldfine AB, Fonseca V, Jablonski KA, Chen YD, Tipton L, Staten MA, Shoelson SE, Targeting Inflammation Using Salsalate in Type 2 Diabetes Study T: Salicylate (salsalate) in patients with type 2 diabetes: a randomized trial. Ann Intern Med 2013;159:1-12
4. Ye J, McGuinness OP: Inflammation during obesity is not all bad: Evidence from animal and human studies. Am J Physiol Endocrinol Metab 2013;304:E466-E477

5/11/2013

Attached is a new paper in Nature Medicine about treatment of insulin resistance with Amlexanox (anti-inflammation medicine) in mice. The paper is an excellent translational study of inflammation in obesity, and also an example to discuss anti-inflammatory medicines. In mice, Amlexanox improved insulin sensitivity. In the mechanism, the drug reduced both inflammation and body weight. This makes it hard to identify which alteration contributes most to the improved insulin sensitivity. The first factor is more important according to authors’ conclusion. However, the second was not excluded in the absence of weight-matched control in the study. Weight loss seems more reasonable in the mechanism as it explains the reduced inflammation and improved insulin sensitivity at the same time.

It will be great to verify the Amlexanox activity in human since there is no literature on it. Amlexanox seems special in the regulation of body weight. Most anti-inflammatory medicines have a common side effect of weight gain in patients. Long-term application of anti-inflammatory medicines induces weight again and increases the risk of obesity. The medicines include glucocorticoids, thiazolidinediones (TZDs), anti-TNFa (infliximab) (1-5), anti-IL6 (6) and nonsteroidal anti-inflammatory medications (NSAIDs) (7). The weight gain is a result of energy accumulation and the mechanism is not completely understood. An increase in food intake may play a role in some case (glucocorticoids), but a reduction in energy expenditure is likely another mechanism.

Reference

1. Renzo LD, Saraceno R, Schipani C, Rizzo M, Bianchi A, Noce A, Esposito M, Tiberti S, Chimenti S, A DEL: Prospective assessment of body weight and body composition changes in patients with psoriasis receiving anti-TNF-alpha treatment. Dermatol Ther 2011;24:446-451
2. Gisondi P, Cotena C, Tessari G, Girolomoni G: Anti-tumour necrosis factor-alpha therapy increases body weight in patients with chronic plaque psoriasis: a retrospective cohort study. J Eur Acad Dermatol Venereol 2008;22:341-344
3. Chen CY, Tsai CY, Lee PC, Lee SD: Long-term Etanercept Therapy Favors Weight Gain and Ameliorates Cachexia in Rheumatoid Arthritis Patients: Roles of Gut Hormones and Leptin. Curr Pharm Des 2013;19:1956-1964
4. Brown RA, Spina D, Butt S, Summers GD: Long-term effects of anti-tumour necrosis factor therapy on weight in patients with rheumatoid arthritis. Clin Rheumatol 2012;31:455-461
5. Florin V, Cottencin AC, Delaporte E, Staumont-Salle D: Body weight increment in patients treated with infliximab for plaque psoriasis. J Eur Acad Dermatol Venereol 2013;27:e186-190
6. Younis S, Rosner I, Rimar D, Boulman N, Rozenbaum M, Odeh M, Slobodin G: Weight change during pharmacological blockade of interleukin-6 or tumor necrosis factor-alpha in patients with inflammatory rheumatic disorders: a 16-week comparative study. Cytokine 2013;61:353-355
7. Wolfe F, Michaud K, Zhao SZ: Patient Perception of the Burden of Weight Gain and Blood Pressure Increase Among RA Patients Using Celecoxib, Rofecoxib, and Non-specific NSAIDs. JCR: Journal of Clinical Rheumatology 2003;9:344-353

4/04/2012

Autophagy has a broad impact in metabolism. A new study suggests that muscle autophagy is induced by exercise. The exercise-induced autophagy is required for muscle performance and metabolic benefits of exercise. Inhibition of the autophagy by BCL2 mutation impairs muscle endurance and increases risk for diet-induced metabolic disorders (1).

Gut epithelial cells controls nutrient absorption and glucose production. They may produce insulin as well according to a recent study of Foxo1 knockout mice. Inducible Foxo1 ablation in adult mice resulted in the generation of gut insulin positive cells. The insulin secreted by these cells is able to reverse hyperglycemia after beta-cell inhibition by streptozotocin (2).

G protein-coupled receptor GPR120 is a receptor for long chain N-3 fatty acids, and mediating N-3 activity in the suppression of inflammatory response. In a new study, inactivation of GPR120 led to enhanced inflammatory response in obese mice (3).KO mice are more obese than Wt control on HFD. Interestingly, KO mice did not show a difference from Wt mice in food intake or energy expenditure. It is not clear where does the extra calorie come from in the KO-induced weight gain?

SIRT1 does not impact life-span in mice. This raised a concern on the relationship of SIRT1 and longevity. A new study suggests that SIRT6 does regulate longevity in mice. Transgenic mice overexpressing Sirt6 have a significantly longer lifespan than wild-type mice (4). This effect is only observed in male, but not female mice.

Reference
1.  He C, Bassik MC, Moresi V, Sun K, Wei Y, Zou Z, An Z, Loh J, Fisher J, Sun Q, Korsmeyer S, Packer M, May HI, Hill JA, Virgin HW, Gilpin C, Xiao G, Bassel-Duby R, Scherer PE, Levine B: Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis. Nature 2012;481:511-515

2.  Talchai C, Xuan S, Kitamura T, Depinho RA, Accili D: Generation of functional insulin-producing cells in the gut by Foxo1 ablation. Nature genetics 2012;44:406-412

3.  Ichimura A, Hirasawa A, Poulain-Godefroy O, Bonnefond A, Hara T, Yengo L, Kimura I, Leloire A, Liu N, Iida K, et al: Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human. Nature 2012;483:350-354

4.  Kanfi Y, Naiman S, Amir G, Peshti V, Zinman G, Nahum L, Bar-Joseph Z, Cohen HY: The sirtuin SIRT6 regulates lifespan in male mice. Nature 2012;483:218-221

1/12/2012

IRIG: 2011 is “brown fat” year 

Obesity is a consequence of energy balance disorder in the body. The disbalance occurs between energy storage and energy expenditure.  If the white adipose tissue stores all the energy of fatty acid and glucose in adipocytes as triglycerides, there will be no problem. Unfortunately, the white adipose tissue growth has a limitation that is reflected by BMI threshold. When this limit is reached, the energy surplus (fatty acid and glucose), if it stays in the body, will generate problems such as chronic inflammation, insulin resistance, hyperlipidemia, hyperglycemia, hypertension, et al. The best prevention is to get rid of the energy surplus. Physical exercise and caloric restriction are the most powerful treatments, which require a strong personal commitment. Therefore, these therapies cannot apply to everybody. Then, other option is to burn energy surplus through brown fat, whose physiological function is to maintain the body temperature by burning fat and glucose. The question is that we do not have many safe and effective medicines in the regulation of brown fat function. To address this issue, brown fat study has been a hot topic in the obesity field. This is indicated by 18 published studies in 2011 in the mainstream journals (Nature, Nature Medicine, Cell metabolism, PNAC, et al).  In addition, at Nature online, a study shows that a new myokine (irisin) is generated in muscle to stimulate white to brown transition in adipose tissue (1).    

Reference [1-19]

1.  Bostrom, P., et al., A PGC1-[agr]-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature, 2012. advance online publication.

2.  Bartness, T.J., A potential link between dorsomedial hypothalamic nucleus NPY and energy balance. Cell metabolism, 2011. 13(5): p. 493-4.

3.  Cao, L., et al., White to brown fat phenotypic switch induced by genetic and environmental activation of a hypothalamic-adipocyte axis. Cell metabolism, 2011. 14(3): p. 324-38.

4.  Chao, P.T., et al., Knockdown of NPY expression in the dorsomedial hypothalamus promotes development of brown adipocytes and prevents diet-induced obesity. Cell metabolism, 2011. 13(5): p. 573-83.

5.  Jimenez-Preitner, M., et al., Plac8 is an inducer of C/EBPbeta required for brown fat differentiation, thermoregulation, and control of body weight. Cell metabolism, 2011. 14(5): p. 658-70.

6.  Moreno-Aliaga, M.J., et al., Cardiotrophin-1 is a key regulator of glucose and lipid metabolism. Cell metabolism, 2011. 14(2): p. 242-53.

7.  Nedergaard, J., T. Bengtsson, and B. Cannon, New powers of brown fat: fighting the metabolic syndrome. Cell metabolism, 2011. 13(3): p. 238-40.

8.  Rose, A.J., et al., Molecular control of systemic bile acid homeostasis by the liver glucocorticoid receptor. Cell metabolism, 2011. 14(1): p. 123-30.

9.  Sellayah, D., P. Bharaj, and D. Sikder, Orexin is required for brown adipose tissue development, differentiation, and function. Cell metabolism, 2011. 14(4): p. 478-90.

10.  Yadav, H., et al., Protection from Obesity and Diabetes by Blockade of TGF-beta/Smad3 Signaling. Cell metabolism, 2011. 14(1): p. 67-79.

11.  Zhang, Z., et al., Neuronal Receptor Activity–Modifying Protein 1 Promotes Energy Expenditure in Mice. Diabetes, 2011. 60(4): p. 1063-1071. 

12.  Hoy, A.J., et al., Adipose Triglyceride Lipase-Null Mice Are Resistant to High-Fat Diet-Induced Insulin Resistance Despite Reduced Energy Expenditure and Ectopic Lipid Accumulation. Endocrinology, 2011. 152(1): p. 48-58.

13.  Seale, P., et al., Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice. The Journal of clinical investigation, 2011. 121(1): p. 96-105.

14.  Cannon, B. and J. Nedergaard, Nonshivering thermogenesis and its adequate measurement in metabolic studies. Journal of Experimental Biology, 2011. 214(Pt 2): p. 242-53.

15.  Nguyen, K.D., et al., Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis. Nature, 2011. 480(7375): p. 104-108.

16.  Bartelt, A., et al., Brown adipose tissue activity controls triglyceride clearance. Nature medicine, 2011. 17(2): p. 200-5.

17.  Fang, S., et al., Corepressor SMRT promotes oxidative phosphorylation in adipose tissue and protects against diet-induced obesity and insulin resistance. Proc Natl Acad Sci U S A, 2011. 108(8): p. 3412-7.

18.  Korach-Andre, M., et al., Both liver-X receptor (LXR) isoforms control energy expenditure by regulating brown adipose tissue activity. Proceedings of the National Academy of Sciences of the United States of America, 2011. 108(1): p. 403-8.

19.  Schulz, T.J., et al., Identification of inducible brown adipocyte progenitors residing in skeletal muscle and white fat. Proceedings of the National Academy of Sciences of the United States of America, 2011. 108(1): p. 143-8. 

12/23/2011

In the current issue of Cell, a short summary is published to introduce several recent papers on brown fat. The link is here: http://www.sciencedirect.com/science/article/pii/S0092867411015133#sec1

SIRT1 is a hot molecular in aging and metabolism fields. SIRT1 was first identified as a longevity gene, whose expression was found to increase lifespan in yeast. This SIRT1 activity is contraversial in a  recent paper in Science (1). It seems that the longevity activity cannot be confirmed by some laboratories in yeast. However, the original study did promote research into the metabolic activities of SIRT1, which has been found to regulate fatty acid metabolism (2). SIRT1 activity is regulated by protein phosphorylation, ubiquitination and proteasome-mediated degradation (3). The serine kinase JNK regulates SIRT1 activity in this way. In obesity, over activation of JNK leads to SIRT1 degradation in the mechanism of fatty liver. In brain, SIRT1 controls mood and behavior (4). Below are the related references.

Reference

1.  Couzin-Frankel J: Aging Genes: The Sirtuin Story Unravels. Science 2011;334:1194-1198

2.  Gerhart-Hines Z, Dominy John E, Blättler Sharon M, Jedrychowski Mark P, Banks Alexander S, Lim J-H, Chim H, Gygi Steven P, Puigserver P: The cAMP/PKA Pathway Rapidly Activates SIRT1 to Promote Fatty Acid Oxidation Independently of Changes in NAD+. Molecular Cell 2011;44:851-863 3.

3.  Gao Z, Zhang J, Kheterpal I, Kennedy N, Davis RJ, Ye J: Sirtuin 1 (SIRT1) degradation in response to persistent JNK1 activation contributes to hepatic steatosis in obesity. Journal of biological chemistry 2011;286:22227-22234

4.  Libert S, Pointer K, Bell Eric L, Das A, Cohen Dena E, Asara John M, Kapur K, Bergmann S, Preisig M, Otowa T, Kendler Kenneth S, Chen X, Hettema John M, van den Oord Edwin J, Rubio JP, Guarente L: SIRT1 Activates MAO-A in the Brain to Mediate Anxiety and Exploratory Drive. Cell 2011;147:1459-1472

Merry Christmas!

By Jianping