Adipose Tissue Abstracts 1


Ursolic Acid-induced elevation of serum irisin augments muscle strength during resistance training in men.
            (Bang et al., 2014) Download
Ursolic acid (UA), a type of pentacyclic triterpenoid carboxylic acid purified from natural plants, can promote skeletal muscle development. We measured the effect of resistance training (RT) with/without UA on skeletal muscle development and related factors in men. Sixteen healthy male participants (age, 29.37±5.14 years; body mass index=27.13±2.16 kg/m(2)) were randomly assigned to RT (n=7) or RT with UA (RT+UA, n=9) groups. Both groups completed 8 weeks of intervention consisting of 5 sets of 26 exercises, with 10~15 repetitions at 60~80% of 1 repetition maximum and a 60~90-s rest interval between sets, performed 6 times/week. UA or placebo was orally ingested as 1 capsule 3 times/day for 8 weeks. The following factors were measured pre-and post-intervention: body composition, insulin, insulin-like growth factor-1 (IGF-1), irisin, and skeletal muscle strength. Body fat percentage was significantly decreased (p<0.001) in the RT+UA group, despite body weight, body mass index, lean body mass, glucose, and insulin levels remaining unchanged. IGF-1 and irisin were significantly increased compared with baseline levels in the RT+UA group (p<0.05). Maximal right and left extension (p<0.01), right flexion (p<0.05), and left flexion (p<0.001) were significantly increased compared with baseline levels in the RT+UA group. These findings suggest that UA-induced elevation of serum irisin may be useful as an agent for the enhancement of skeletal muscle strength during RT.

A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis.
            (Boström et al., 2012) Download
Exercise benefits a variety of organ systems in mammals, and some of the best-recognized effects of exercise on muscle are mediated by the transcriptional co-activator PPAR-γ co-activator-1 α (PGC1-α). Here we show in mouse that PGC1-α expression in muscle stimulates an increase in expression of FNDC5, a membrane protein that is cleaved and secreted as a newly identified hormone, irisin. Irisin acts on white adipose cells in culture and in vivo to stimulate UCP1 expression and a broad program of brown-fat-like development. Irisin is induced with exercise in mice and humans, and mildly increased irisin levels in the blood cause an increase in energy expenditure in mice with no changes in movement or food intake. This results in improvements in obesity and glucose homeostasis. Irisin could be therapeutic for human metabolic disease and other disorders that are improved with exercise.

Identification and importance of brown adipose tissue in adult humans.
            (Cypess et al., 2009) Download
BACKGROUND:  Obesity results from an imbalance between energy intake and expenditure. In rodents and newborn humans, brown adipose tissue helps regulate energy expenditure by thermogenesis mediated by the expression of uncoupling protein 1 (UCP1), but brown adipose tissue has been considered to have no physiologic relevance in adult humans. METHODS:  We analyzed 3640 consecutive (18)F-fluorodeoxyglucose ((18)F-FDG) positron-emission tomographic and computed tomographic (PET-CT) scans performed for various diagnostic reasons in 1972 patients for the presence of substantial depots of putative brown adipose tissue. Such depots were defined as collections of tissue that were more than 4 mm in diameter, had the density of adipose tissue according to CT, and had maximal standardized uptake values of (18)F-FDG of at least 2.0 g per milliliter, indicating high metabolic activity. Clinical indexes were recorded and compared with those of date-matched controls. Immunostaining for UCP1 was performed on biopsy specimens from the neck and supraclavicular regions in patients undergoing surgery. RESULTS:  Substantial depots of brown adipose tissue were identified by PET-CT in a region extending from the anterior neck to the thorax. Tissue from this region had UCP1-immunopositive, multilocular adipocytes indicating brown adipose tissue. Positive scans were seen in 76 of 1013 women (7.5%) and 30 of 959 men (3.1%), corresponding to a female:male ratio greater than 2:1 (P<0.001). Women also had a greater mass of brown adipose tissue and higher (18)F-FDG uptake activity. The probability of the detection of brown adipose tissue was inversely correlated with years of age (P<0.001), outdoor temperature at the time of the scan (P=0.02), beta-blocker use (P<0.001), and among older patients, body-mass index (P=0.007). CONCLUSIONS:  Defined regions of functionally active brown adipose tissue are present in adult humans, are more frequent in women than in men, and may be quantified noninvasively with the use of (18)F-FDG PET-CT. Most important, the amount of brown adipose tissue is inversely correlated with body-mass index, especially in older people, suggesting a potential role of brown adipose tissue in adult human metabolism.

Dietary fats and adipose tissue fatty acid composition.
            (Hashim, 1983) Download

Ursolic acid increases skeletal muscle and brown fat and decreases diet-induced obesity, glucose intolerance and fatty liver disease.
            (Kunkel et al., 2012) Download
Skeletal muscle Akt activity stimulates muscle growth and imparts resistance to obesity, glucose intolerance and fatty liver disease. We recently found that ursolic acid increases skeletal muscle Akt activity and stimulates muscle growth in non-obese mice. Here, we tested the hypothesis that ursolic acid might increase skeletal muscle Akt activity in a mouse model of diet-induced obesity. We studied mice that consumed a high fat diet lacking or containing ursolic acid. In skeletal muscle, ursolic acid increased Akt activity, as well as downstream mRNAs that promote glucose utilization (hexokinase-II), blood vessel recruitment (Vegfa) and autocrine/paracrine IGF-I signaling (Igf1). As a result, ursolic acid increased skeletal muscle mass, fast and slow muscle fiber size, grip strength and exercise capacity. Interestingly, ursolic acid also increased brown fat, a tissue that shares developmental origins with skeletal muscle. Consistent with increased skeletal muscle and brown fat, ursolic acid increased energy expenditure, leading to reduced obesity, improved glucose tolerance and decreased hepatic steatosis. These data support a model in which ursolic acid reduces obesity, glucose intolerance and fatty liver disease by increasing skeletal muscle and brown fat, and suggest ursolic acid as a potential therapeutic approach for obesity and obesity-related illness.

The effects of hedonically acceptable red pepper doses on thermogenesis and appetite.
            (Ludy and Mattes, 2011) Download
Previous studies suggest consumption of red pepper (RP) promotes negative energy balance. However, the RP dose provided in these studies (up to 10 g/meal) usually exceeded the amount preferred by the general population in the United States (mean=~1 g/meal). The objective of this study was to evaluate the effects of hedonically acceptable RP doses served at a single meal in healthy, lean individuals on thermogenesis and appetite. Twenty-five men and women (aged 23.0 ± 0.5 years, BMI 22.6 ± 0.3 kg/m(2), 13 spicy food users and 12 non-users) participated in a randomized crossover trial during which they consumed a standardized quantity (1 g); their preferred quantity (regular spicy food users 1.8 ± 0.3 g/meal, non-users 0.3 ± 0.1 g/meal); or no RP. Energy expenditure, core body and skin temperature, and appetite were measured. Postprandial energy expenditure and core body temperature were greater, and skin temperature was lower, after test loads with 1 g RP than no RP. Respiratory quotient was lower after the preferred RP dose was ingested orally, compared to in capsule form. These findings suggest that RP's effects on energy balance stem from a combination of metabolic and sensory inputs, and that oral exposure is necessary to achieve RP's maximum benefits. Energy intake was lower after test loads with 1 g RP than no RP in non-users, but not in users. Preoccupation with food, and the desire to consume fatty, salty, and sweet foods were decreased more (or tended to be decreased more) in non-users than users after a 1 g RP test load, but did not vary after a test load with no RP. This suggests that individuals may become desensitized to the effects of RP with long-term spicy food intake.

Anterograde transneuronal viral tract tracing reveals central sensory circuits from brown fat and sensory denervation alters its thermogenic responses.
            (Vaughan and Bartness, 2012) Download
Brown adipose tissue (BAT) thermogenic activity and growth are controlled by its sympathetic nervous system (SNS) innervation, but nerve fibers containing sensory-associated neuropeptides [substance P, calcitonin gene-related peptide (CGRP)] also suggest sensory innervation. The central nervous system (CNS) projections of BAT afferents are unknown. Therefore, we used the H129 strain of the herpes simplex virus-1 (HSV-1), an anterograde transneuronal viral tract tracer used to delineate sensory nerve circuits, to define these projections. HSV-1 was injected into interscapular BAT (IBAT) of Siberian hamsters and HSV-1 immunoreactivity (ir) was assessed 24, 48, 72, 96, and 114 h postinjection. The 96- and 114-h groups had the most HSV-1-ir neurons with marked infections in the hypothalamic paraventricular nucleus, periaqueductal gray, olivary areas, parabrachial nuclei, raphe nuclei, and reticular areas. These sites also are involved in sympathetic outflow to BAT suggesting possible BAT sensory-SNS thermogenesis feedback circuits. We tested the functional contribution of IBAT sensory innervation on thermogenic responses to an acute (24 h) cold exposure test by injecting the specific sensory nerve toxin capsaicin directly into IBAT pads and then measuring core (T(c)) and IBAT (T(IBAT)) temperature responses. CGRP content was significantly decreased in capsaicin-treated IBAT demonstrating successful sensory nerve destruction. T(IBAT) and T(c) were significantly decreased in capsaicin-treated hamsters compared with the saline controls at 2 h of cold exposure. Thus the central sensory circuits from IBAT have been delineated for the first time, and impairment of sensory feedback from BAT appears necessary for the appropriate, initial thermogenic response to acute cold exposure.

Resveratrol induces brown-like adipocyte formation in white fat through activation of AMP-activated protein kinase (AMPK) α1.
            (Wang et al., 2015) Download
OBJECTIVE:  Development of brown-like/beige adipocytes in white adipose tissue (WAT) helps to reduce obesity. Thus we investigated the effects of resveratrol, a dietary polyphenol capable of preventing obesity and related complications in humans and animal models, on brown-like adipocyte formation in inguinal WAT (iWAT). METHODS:  CD1 female mice (5-month old) were fed a high-fat diet with/without 0.1% resveratrol. In addition, primary stromal vascular cells separated from iWAT were subjected to resveratrol treatment. Markers of brown-like (beige) adipogenesis were measured and the involvement of AMP-activated protein kinase (AMPK) α1 was assessed using conditional knockout. RESULTS:  Resveratrol significantly increased mRNA and/or protein expression of brown adipocyte markers, including uncoupling protein 1 (UCP1), PR domain-containing 16, cell death-inducing DFFA-like effector A, elongation of very long-chain fatty acids protein 3, peroxisome proliferator-activated receptor-γ coactivator 1α, cytochrome c and pyruvate dehydrogenase, in differentiated iWAT stromal vascular cells (SVCs), suggesting that resveratrol induced brown-like adipocyte formation in vitro. Concomitantly, resveratrol markedly enhanced AMPKα1 phosphorylation and differentiated SVC oxygen consumption. Such changes were absent in cells lacking AMPKα1, showing that AMPKα1 is a critical mediator of resveratrol action. Resveratrol also induced beige adipogenesis in vivo along with the appearance of multiocular adipocytes, increased UCP1 expression and enhanced fatty acid oxidation. CONCLUSIONS:  Resveratrol induces brown-like adipocyte formation in iWAT via AMPKα1 activation and suggest that its beneficial antiobesity effects may be partly due to the browning of WAT and, as a consequence, increased oxygen consumption.

Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human.
            (Wu et al., 2012) Download
Brown fat generates heat via the mitochondrial uncoupling protein UCP1, defending against hypothermia and obesity. Recent data suggest that there are two distinct types of brown fat: classical brown fat derived from a myf-5 cellular lineage and UCP1-positive cells that emerge in white fat from a non-myf-5 lineage. Here, we report the isolation of "beige" cells from murine white fat depots. Beige cells resemble white fat cells in having extremely low basal expression of UCP1, but, like classical brown fat, they respond to cyclic AMP stimulation with high UCP1 expression and respiration rates. Beige cells have a gene expression pattern distinct from either white or brown fat and are preferentially sensitive to the polypeptide hormone irisin. Finally, we provide evidence that previously identified brown fat deposits in adult humans are composed of beige adipocytes. These data provide a foundation for studying this mammalian cell type with therapeutic potential. PAPERCLIP

Irisin ERKs the fat.
            (Wu and Spiegelman, 2014) Download
Comment on: Zhang 2014 - Irisin stimulates browning of white adipocyte

Nonpungent capsaicin analogs (capsinoids) increase energy expenditure through the activation of brown adipose tissue in humans.
            (Yoneshiro et al., 2012) Download
BACKGROUND:  Capsinoids-nonpungent capsaicin analogs-are known to activate brown adipose tissue (BAT) thermogenesis and whole-body energy expenditure (EE) in small rodents. BAT activity can be assessed by [¹⁸F]fluorodeoxyglucose-positron emission tomography (FDG-PET) in humans. OBJECTIVES:  The aims of the current study were to examine the acute effects of capsinoid ingestion on EE and to analyze its relation to BAT activity in humans. DESIGN:  Eighteen healthy men aged 20-32 y underwent FDG-PET after 2 h of cold exposure (19°C) while wearing light clothing. Whole-body EE and skin temperature, after oral ingestion of capsinoids (9 mg), were measured for 2 h under warm conditions (27°C) in a single-blind, randomized, placebo-controlled, crossover design. RESULTS:  When exposed to cold, 10 subjects showed marked FDG uptake into adipose tissue of the supraclavicular and paraspinal regions (BAT-positive group), whereas the remaining 8 subjects (BAT-negative group) showed no detectable uptake. Under warm conditions (27°C), the mean (±SEM) resting EE was 6114 ± 226 kJ/d in the BAT-positive group and 6307 ± 156 kJ/d in the BAT-negative group (NS). EE increased by 15.2 ± 2.6 kJ/h in 1 h in the BAT-positive group and by 1.7 ± 3.8 kJ/h in the BAT-negative group after oral ingestion of capsinoids (P < 0.01). Placebo ingestion produced no significant change in either group. Neither capsinoids nor placebo changed the skin temperature in various regions, including regions close to BAT deposits. CONCLUSION:  Capsinoid ingestion increases EE through the activation of BAT in humans. This trial was registered at as UMIN 000006073.

Transient receptor potential activated brown fat thermogenesis as a target of food ingredients for obesity management.
            (Yoneshiro and Saito, 2013) Download
PURPOSE OF REVIEW:  Cold exposure activates brown adipose tissue (BAT), the major site of sympathetically activated nonshivering thermognenesis, via transient receptor potential (TRP) channels. Capsaicin and its nonpungent analogue (capsinoids) are agonists for a vanilloid subtype one of TRP, and have the potential to increase whole-body energy expenditure and reduce body fat. This article reviews the regulatory roles of BAT for energy expenditure and body fat in humans, particularly focusing on food ingredients activating the TRP-BAT axis. RECENT FINDINGS:  Acute cold exposure increased energy expenditure in humans with metabolically active BAT, but not those without it. Quite similar responses were found after a single oral ingestion of either capsinoids or an alcohol extract of Guinea pepper seeds, indicating that these food ingredients activate BAT and thereby increase energy expenditure. When individuals without active BAT were exposed to cold every day for 6 weeks, BAT was recruited in association with increased energy expenditure and decreased body fat. A 6-week daily ingestion of capsinoids mimicked the effects of repeated cold exposure. These findings indicate that human BAT can be reactivated/recruited, thereby increasing energy expenditure and decreasing body fat. SUMMARY:  Human BAT recruited by prolonged ingestion of a vanilloid subtype one of TRP agonists increases energy expenditure and decreases body fat. In addition to capsinoids, there are numerous food ingredients acting as TRP agonists, which are expected to activate BAT and so be useful for the prevention of obesity in daily life.

Irisin stimulates browning of white adipocytes through mitogen-activated protein kinase p38 MAP kinase and ERK MAP kinase signaling.
            (Zhang et al., 2014a) Download
The number and activity of brown adipocytes are linked to the ability of mammals to resist body fat accumulation. In some conditions, certain white adipose tissue (WAT) depots are readily convertible to a ''brown-like'' state, which is associated with weight loss. Irisin, a newly identified hormone, is secreted by skeletal muscles into circulation and promotes WAT "browning" with unknown mechanisms. In the current study, we demonstrated in mice that recombinant irisin decreased the body weight and improved glucose homeostasis. We further showed that irisin upregulated uncoupling protein-1 (UCP-1; a regulator of thermogenic capability of brown fat) expression. This effect was possibly mediated by irisin-induced phosphorylation of the p38 mitogen-activated protein kinase (p38 MAPK) and extracellular signal-related kinase (ERK) signaling pathways. Inhibition of the p38 MAPK by SB203580 and ERK by U0126 abolished the upregulatory effect of irisin on UCP-1. In addition, irisin also promoted the expression of betatrophin, another newly identified hormone that promotes pancreatic β-cell proliferation and improves glucose tolerance. In summary, our data suggest that irisin can potentially prevent obesity and associated type 2 diabetes by stimulating expression of WAT browning-specific genes via the p38 MAPK and ERK pathways.

Berberine activates thermogenesis in white and brown adipose tissue.
            (Zhang et al., 2014b) Download
Obesity develops when energy intake exceeds energy expenditure. Promoting brown adipose tissue formation and function increases energy expenditure and hence may counteract obesity. Berberine (BBR) is a compound derived from the Chinese medicinal plant Coptis chinensis. Here we show that BBR increases energy expenditure, limits weight gain, improves cold tolerance and enhances brown adipose tissue (BAT) activity in obese db/db mice. BBR markedly induces the development of brown-like adipocytes in inguinal, but not epididymal adipose depots. BBR also increases expression of UCP1 and other thermogenic genes in white and BAT and primary adipocytes via a mechanism involving AMPK and PGC-1α. BBR treatment also inhibits AMPK activity in the hypothalamus, but genetic activation of AMPK in the ventromedial nucleus of the hypothalamus does not prevent BBR-induced weight loss and activation of the thermogenic programme. Our findings establish a role for BBR in regulating organismal energy balance, which may have potential therapeutic implications for the treatment of obesity.



Bang, HS, et al. (2014), ‘Ursolic Acid-induced elevation of serum irisin augments muscle strength during resistance training in men.’, Korean J Physiol Pharmacol, 18 (5), 441-46. PubMedID: 25352765
Boström, P, et al. (2012), ‘A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis.’, Nature, 481 (7382), 463-68. PubMedID: 22237023
Cypess, AM, et al. (2009), ‘Identification and importance of brown adipose tissue in adult humans.’, N Engl J Med, 360 (15), 1509-17. PubMedID: 19357406
Hashim, SA (1983), ‘Dietary fats and adipose tissue fatty acid composition.’, Prev Med, 12 (6), 854-67. PubMedID: 6676733
Kunkel, SD, et al. (2012), ‘Ursolic acid increases skeletal muscle and brown fat and decreases diet-induced obesity, glucose intolerance and fatty liver disease.’, PLoS One, 7 (6), e39332. PubMedID: 22745735
Ludy, MJ and RD Mattes (2011), ‘The effects of hedonically acceptable red pepper doses on thermogenesis and appetite.’, Physiol Behav, 102 (3-4), 251-58. PubMedID: 21093467
Vaughan, CH and TJ Bartness (2012), ‘Anterograde transneuronal viral tract tracing reveals central sensory circuits from brown fat and sensory denervation alters its thermogenic responses.’, Am J Physiol Regul Integr Comp Physiol, 302 (9), R1049-58. PubMedID: 22378771
Wang, S, et al. (2015), ‘Resveratrol induces brown-like adipocyte formation in white fat through activation of AMP-activated protein kinase (AMPK) α1.’, Int J Obes (Lond), 39 (6), 967-76. PubMedID: 25761413
Wu, J, et al. (2012), ‘Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human.’, Cell, 150 (2), 366-76. PubMedID: 22796012
Wu, J and BM Spiegelman (2014), ‘Irisin ERKs the fat.’, Diabetes, 63 (2), 381-83. PubMedID: 24464712
Yoneshiro, T, et al. (2012), ‘Nonpungent capsaicin analogs (capsinoids) increase energy expenditure through the activation of brown adipose tissue in humans.’, Am J Clin Nutr, 95 (4), 845-50. PubMedID: 22378725
Yoneshiro, T and M Saito (2013), ‘Transient receptor potential activated brown fat thermogenesis as a target of food ingredients for obesity management.’, Curr Opin Clin Nutr Metab Care, 16 (6), 625-31. PubMedID: 24100669
Zhang, Y, et al. (2014a), ‘Irisin stimulates browning of white adipocytes through mitogen-activated protein kinase p38 MAP kinase and ERK MAP kinase signaling.’, Diabetes, 63 (2), 514-25. PubMedID: 24150604
Zhang, Z, et al. (2014b), ‘Berberine activates thermogenesis in white and brown adipose tissue.’, Nat Commun, 5 5493. PubMedID: 25423280