Withania somnifera Extract Enhances Energy Expenditure via Improving Mitochondrial Function in Adipose Tissue and Skeletal Muscle

Withania somnifera (WS), commonly known as ashwagandha, possesses diverse biological functions. WS root has mainly been used as an herbal medicine to treat anxiety and was recently reported to have an anti-obesity effect, however, the mechanisms underlying its action remain to be explored. We hypothesized that WS exerts its anti-obesity effect by enhancing energy expenditure through improving the mitochondrial function of brown/beige adipocytes and skeletal muscle. Male C57BL/6J mice were fed a high-fat diet (HFD) containing 0.25% or 0.5% WS 70% ethanol extract (WSE) for 10 weeks. WSE (0.5%) supplementation significantly suppressed the increases in body weight and serum lipids, and lipid accumulation in the liver and adipose tissue induced by HFD. WSE supplementation increased oxygen consumption and enhanced mitochondrial activity in brown fat and skeletal muscle in the HFD-fed mice. In addition, it promoted browning of subcutaneous fat by increasing mitochondrial uncoupling protein 1 (UCP1) expression. Withaferin A (WFA), a major compound of WS, enhanced the differentiation of pre-adipocytes into beige adipocytes and oxygen consumption in C2C12 murine myoblasts. These results suggest that WSE ameliorates diet-induced obesity by enhancing energy expenditure via promoting mitochondrial function in adipose tissue and skeletal muscle, and WFA is a key regulator in this function.

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Adipose and skeletal muscle thermogenesis: studies from large animals

Journal of Endocrinology ◽

10.1530/joe-18-0090 ◽

2018 ◽

Vol 237 (3) ◽

pp. R99-R115 ◽

Cited By ~ 21

Author(s):

John-Paul Fuller-Jackson ◽

Belinda A Henry

Keyword(s):

Skeletal Muscle ◽

Body Weight ◽

Adipose Tissue ◽

Energy Expenditure ◽

Heat Dissipation ◽

Uncoupling Protein ◽

Calcium Cycling ◽

Fat Depots ◽

Brown Adipose ◽

Beige Adipocytes

The balance between energy intake and energy expenditure establishes and preserves a ‘set-point’ body weight. The latter is comprised of three major components including metabolic rate, physical activity and thermogenesis. Thermogenesis is defined as the cellular dissipation of energy via heat production. This process has been extensively characterised in brown adipose tissue (BAT), wherein uncoupling protein 1 (UCP1) creates a proton leak across the inner mitochondrial membrane, diverting protons away from ATP synthesis and resulting in heat dissipation. In beige adipocytes and skeletal muscle, thermogenesis can occur independent of UCP1. Beige adipocytes have been shown to produce heat via UCP1 as well as via both futile creatine and calcium cycling pathways. On the other hand, the UCP1 homologue UCP3 is abundant in skeletal muscle and post-prandial thermogenesis has been associated with UCP3 and the futile calcium cycling. This review will focus on the differential contributions of adipose tissue and skeletal muscle in determining total thermogenic output and energy expenditure in large mammals. Sheep and pigs do not have a circumscribed brown fat depot but rather possess white fat depots that contain brown and beige adipocytes interspersed amongst white adipose tissue. This is representative of humans, where brown, beige and white adipocytes have been identified in the neck and supraclavicular regions. This review will describe the mechanisms of thermogenesis in pigs and sheep and the relative roles of skeletal muscle and adipose tissue thermogenesis in controlling body weight in larger mammals.

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A compendium of G-protein–coupled receptors and cyclic nucleotide regulation of adipose tissue metabolism and energy expenditure

Clinical Science ◽

10.1042/cs20190579 ◽

2020 ◽

Vol 134 (5) ◽

pp. 473-512 ◽

Cited By ~ 5

Author(s):

Ryan P. Ceddia ◽

Sheila Collins

Keyword(s):

Adipose Tissue ◽

Energy Expenditure ◽

Signaling Pathways ◽

G Protein ◽

Uncoupling Protein ◽

Beige Adipocytes ◽

Nucleotide Regulation ◽

Ucp1 Expression ◽

Thermogenic Adipocytes ◽

G Protein Coupled

Abstract With the ever-increasing burden of obesity and Type 2 diabetes, it is generally acknowledged that there remains a need for developing new therapeutics. One potential mechanism to combat obesity is to raise energy expenditure via increasing the amount of uncoupled respiration from the mitochondria-rich brown and beige adipocytes. With the recent appreciation of thermogenic adipocytes in humans, much effort is being made to elucidate the signaling pathways that regulate the browning of adipose tissue. In this review, we focus on the ligand–receptor signaling pathways that influence the cyclic nucleotides, cAMP and cGMP, in adipocytes. We chose to focus on G-protein–coupled receptor (GPCR), guanylyl cyclase and phosphodiesterase regulation of adipocytes because they are the targets of a large proportion of all currently available therapeutics. Furthermore, there is a large overlap in their signaling pathways, as signaling events that raise cAMP or cGMP generally increase adipocyte lipolysis and cause changes that are commonly referred to as browning: increasing mitochondrial biogenesis, uncoupling protein 1 (UCP1) expression and respiration.

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Egr1 loss-of-function promotes beige adipocyte differentiation and activation specifically in inguinal subcutaneous white adipose tissue

Scientific Reports ◽

10.1038/s41598-020-72698-w ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Marianne Bléher ◽

Berbang Meshko ◽

Isabelle Cacciapuoti ◽

Rachel Gergondey ◽

Yoann Kovacs ◽

...

Keyword(s):

Adipose Tissue ◽

White Adipose Tissue ◽

Adipocyte Differentiation ◽

Uncoupling Protein ◽

Subcutaneous Fat ◽

Loss Of Function ◽

Beige Adipocyte ◽

Subcutaneous White Adipose Tissue ◽

Fat Depots ◽

Beige Adipocytes

Abstract In mice, exercise, cold exposure and fasting lead to the differentiation of inducible-brown adipocytes, called beige adipocytes, within white adipose tissue and have beneficial effects on fat burning and metabolism, through heat production. This browning process is associated with an increased expression of the key thermogenic mitochondrial uncoupling protein 1, Ucp1. Egr1 transcription factor has been described as a regulator of white and beige differentiation programs, and Egr1 depletion is associated with a spontaneous increase of subcutaneous white adipose tissue browning, in absence of external stimulation. Here, we demonstrate that Egr1 mutant mice exhibit a restrained Ucp1 expression specifically increased in subcutaneous fat, resulting in a metabolic shift to a more brown-like, oxidative metabolism, which was not observed in other fat depots. In addition, Egr1 is necessary and sufficient to promote white and alter beige adipocyte differentiation of mouse stem cells. These results suggest that modulation of Egr1 expression could represent a promising therapeutic strategy to increase energy expenditure and to restrain obesity-associated metabolic disorders.

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Egr1 loss-of-function promotes beige adipocyte differentiation and activation specifically in inguinal subcutaneous white adipose tissue

10.1101/2020.06.03.131342 ◽

2020 ◽

Author(s):

Marianne Bléher ◽

Berbang Meshko ◽

Rachel Gergondey ◽

Yoann Kovacs ◽

Delphine Duprez ◽

...

Keyword(s):

Adipose Tissue ◽

White Adipose Tissue ◽

Adipocyte Differentiation ◽

Uncoupling Protein ◽

Subcutaneous Fat ◽

Loss Of Function ◽

Beige Adipocyte ◽

Subcutaneous White Adipose Tissue ◽

Fat Depots ◽

Beige Adipocytes

AbstractExercise, cold exposure and fasting lead to the differentiation of inducible-brown adipocytes, called beige adipocytes, within white adipose tissue and have beneficial effects on fat burning and metabolism, through heat production. This browning process is associated with an increased expression of the key thermogenic mitochondrial uncoupling protein 1, Ucp1. Egr1 transcription factor has been described as a regulator of white and beige differentiation programs, and Egr1 depletion is associated with a spontaneous increase of subcutaneous white adipose tissue browning, in absence of external stimulation. Here, we demonstrate that Egr1 mutant mice exhibit a restrained Ucp1 expression specifically increased in subcutaneous fat, resulting in a metabolic shift to a more brown-like, oxidative metabolism, which was not observed in other fat depots. In addition, Egr1 is necessary and sufficient to promote white and alter beige adipocyte differentiation of mouse stem cells. These results suggest that modulation of Egr1 expression could represent a promising therapeutic strategy to increase energy expenditure and to restrain obesity-associated metabolic disorders.

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Leptin increases uncoupling protein expression and energy expenditure

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1997.273.1.e226 ◽

1997 ◽

Vol 273 (1) ◽

pp. E226-E230 ◽

Cited By ~ 63

Author(s):

P. J. Scarpace ◽

M. Matheny ◽

B. H. Pollock ◽

N. Tumer

Keyword(s):

Adipose Tissue ◽

Oxygen Consumption ◽

Energy Expenditure ◽

Brown Adipose Tissue ◽

Food Consumption ◽

Uncoupling Protein ◽

Mrna Levels ◽

Sympathetic Outflow ◽

Brown Adipose ◽

Ad Libitum

In ob/ob mice, leptin increases energy expenditure and sympathetic outflow to brown adipose tissue (BAT). To test whether the mechanism of increased energy expenditure may involve increased thermogenesis in BAT, we acclimated normal rats to thermoneutrality for 2 wk followed by leptin administration for 1 wk. Some rats were food restricted for 1 wk to the level of food consumption in the leptin-treated ad libitum-fed rats, and the same rats were both food restricted and administered leptin for a second week. We examined oxygen consumption and uncoupling protein (UCP) expression in BAT. Leptin increased oxygen consumption after the 5th and 6th days in ad libitum-fed rats and after the 4th, 5th, and 6th days in food-restricted rats. Leptin increased BAT UCP mRNA levels greater than twofold in both ad libitum-fed and food-restricted rats. These data demonstrate a leptin-induced increase in energy expenditure in nonmutant rodents and suggest that one mechanism by which leptin increases energy expenditure is through increased thermogenesis in BAT, including increased expression of UCP.

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Supplemental epilactose prevents metabolic disorders through uncoupling protein-1 induction in the skeletal muscle of mice fed high-fat diets

British Journal Of Nutrition ◽

10.1017/s0007114515003505 ◽

2015 ◽

Vol 114 (11) ◽

pp. 1774-1783 ◽

Cited By ~ 18

Author(s):

Yuki Murakami ◽

Teruyo Ojima-Kato ◽

Wataru Saburi ◽

Haruhide Mori ◽

Hirokazu Matsui ◽

...

Keyword(s):

Skeletal Muscle ◽

Adipose Tissue ◽

Energy Expenditure ◽

Brown Adipose Tissue ◽

Propionic Acid ◽

Metabolic Disorders ◽

Uncoupling Protein ◽

C2c12 Cells ◽

High Fat ◽

Brown Adipose

AbstractObesity is one of the major health problems throughout the world. The present study investigated the preventive effect of epilactose – a rare non-digestible disaccharide – on obesity and metabolic disorders in mice fed high-fat (HF) diets. Feeding with HF diets increased body weight gain, fat pad weight and adipocyte size in mice (P<0·01), and these increases were effectively prevented by the use of supplemental epilactose without influencing food intake (P<0·01). Caecal pools of SCFA such as acetic and propionic acids in mice fed epilactose were higher compared with mice not receiving epilactose. Supplemental epilactose increased the expression of uncoupling protein (UCP)-1, which enhances energy expenditure, to 2-fold in the gastrocnemius muscle (P=0·04) and to 1·3-fold in the brown adipose tissue (P=0·02) in mice fed HF diets. Feeding HF diets induced pro-inflammatory macrophage infiltration into white adipose tissue, as indicated by the increased expression of monocyte chemotactic protein-1, TNF-α and F4/80, and these increases were attenuated by supplemental epilactose. In differentiated myogenic-like C2C12 cells, propionic acid, but not acetic or n-butyric acids, directly enhanced UCP-1 expression by approximately 2-fold (P<0·01). Taken together, these findings indicate that the epilactose-mediated increase in UCP-1 in the skeletal muscle and brown adipose tissue can enhance whole-body energy expenditure, leading to effective prevention of obesity and metabolic disorders in mice fed HF diets. It is suggested that propionic acid – a bacterial metabolite – acts as a mediator to induce UCP-1 expression in skeletal muscles.

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Regulation of human subcutaneous adipocyte differentiation by EID1

Journal of Molecular Endocrinology ◽

10.1530/jme-15-0148 ◽

2015 ◽

Vol 56 (2) ◽

pp. 113-122 ◽

Cited By ~ 9

Author(s):

Diana Vargas ◽

Noriaki Shimokawa ◽

Ryosuke Kaneko ◽

Wendy Rosales ◽

Adriana Parra ◽

...

Keyword(s):

Adipose Tissue ◽

Uncoupling Protein ◽

Human Adipose Tissue ◽

Mitochondrial Activity ◽

Mitochondrial Uncoupling ◽

Mitochondrial Uncoupling Protein ◽

Triglyceride Accumulation ◽

White Adipocytes ◽

Beige Adipocytes

Increasing thermogenesis in white adipose tissues can be used to treat individuals at high risk for obesity and cardiovascular disease. The objective of this study was to determine the function of EP300-interacting inhibitor of differentiation (EID1), an inhibitor of muscle differentiation, in the induction of beige adipocytes from adipose mesenchymal stem cells (ADMSCs). Subcutaneous adipose tissue was obtained from healthy women undergoing abdominoplasty. ADMSCs were isolated in vitro, grown, and transfected with EID1 or EID1 siRNA, and differentiation was induced after 48 h by administering rosiglitazone. The effects of EID1 expression under the control of the aP2 promoter (aP2-EID1) were also evaluated in mature adipocytes that were differentiated from ADMSCs. Transfection of EID1 into ADMSCs reduced triglyceride accumulation while increasing levels of thermogenic proteins, such as PGC1α, TFAM, and mitochondrial uncoupling protein 1 (UCP1), all of which are markers of energy expenditure and mitochondrial activity. Furthermore, increased expression of the beige phenotype markers CITED1 and CD137 was observed. Transfection of aP2-EID1 transfection induced the conversion of mature white adipocytes to beige adipocytes, as evidenced by increased expression of PGC1α, UCP1, TFAM, and CITED1. These results indicate that EID1 can modulate ADMSCs, inducing a brown/beige lineage. EID1 may also activate beiging in white adipocytes obtained from subcutaneous human adipose tissue.

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The Role of Uncoupling Protein 1 in the Metabolism and Adiposity of RIIβ-Protein Kinase A-Deficient Mice

Molecular Endocrinology ◽

10.1210/me.2004-0194 ◽

2004 ◽

Vol 18 (9) ◽

pp. 2302-2311 ◽

Cited By ~ 21

Author(s):

Michael A. Nolan ◽

Maria A. Sikorski ◽

G. Stanley McKnight

Keyword(s):

Adipose Tissue ◽

Oxygen Consumption ◽

Protein Kinase ◽

Protein Kinase A ◽

Uncoupling Protein ◽

Mrna Level ◽

Regulatory Subunit ◽

Uncoupling Protein 1 ◽

Brown Adipose ◽

Kinase A

Abstract Mice lacking the RIIβ regulatory subunit of protein kinase A exhibit a 50% reduction in white adipose tissue stores compared with wild-type littermates and are resistant to diet-induced obesity. RIIβ−/− mice also have an increase in resting oxygen consumption along with a 4-fold increase in the brown adipose-specific mitochondrial uncoupling protein 1 (UCP1). In this study, we examined the basis for UCP1 induction and tested the hypothesis that the induced levels of UCP1 in RIIβ null mice are essential for the lean phenotype. The induction of UCP1 occurred at the protein but not the mRNA level and correlated with an increase in mitochondria in brown adipose tissue. Mice lacking both RIIβ and UCP1 (RIIβ−/−/Ucp1−/−) were created, and the key parameters of metabolism and body composition were studied. We discovered that RIIβ−/− mice exhibit nocturnal hyperactivity in addition to the increased oxygen consumption at rest. Disruption of UCP1 in RIIβ−/− mice reduced basal oxygen consumption but did not prevent the nocturnal hyperactivity. The double knockout animals also retained the lean phenotype of the RIIβ null mice, demonstrating that induction of UCP1 and increased resting oxygen consumption is not the cause of leanness in the RIIβ mutant mice.

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Influence of age, fat cell weight, and obesity on O2 consumption of human adipose tissue

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1989.256.4.e467 ◽

1989 ◽

Vol 256 (4) ◽

pp. E467-E474 ◽

Cited By ~ 6

Author(s):

P. Hallgren ◽

L. Sjostrom ◽

H. Hedlund ◽

L. Lundell ◽

L. Olbe

Keyword(s):

Adipose Tissue ◽

Oxygen Consumption ◽

Energy Expenditure ◽

Human Adipose Tissue ◽

Fat Cell ◽

Cell Weight ◽

Total Body ◽

Obese Human ◽

Open Question ◽

Partial Weight

The oxygen consumption of human adipose tissue (AT) was determined in 53 adults, lean and obese, and in nine lean boys. The oxygen consumption was positively related to fat cell weight and negatively to age and degree of obesity. Men and women did not differ with respect to oxygen consumption of AT. The positive relationship between oxygen consumption per cell and fat cell size was also demonstrated in size-separated cells from the same donors. Expressed per cell the oxygen consumption was higher in fat cells from obese than in cells from lean subjects, but expressed per gram of tissue the opposite result was found. The oxygen consumption of the total AT organ was higher in obese than in lean subjects. The energy expenditure of AT constituted approximately 4% of the estimated 24-h energy expenditure in both groups. It is concluded that obese subjects do not maintain their obesity because of a reduced energy expenditure of the total AT (or of the total body). After a partial weight reduction in five subjects, the energy metabolism tended to change in direction toward the conditions seen in lean subjects. However, it is still an open question whether the observed energy metabolic aberrations of obese human AT are only secondary to the obese state or partly primary and thus of etiological importance.

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Thermogenic response to epinephrine in the forearm and abdominal subcutaneous adipose tissue

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1992.263.5.e850 ◽

1992 ◽

Vol 263 (5) ◽

pp. E850-E855 ◽

Cited By ~ 13

Author(s):

L. Simonsen ◽

J. Bulow ◽

J. Madsen ◽

N. J. Christensen

Keyword(s):

Skeletal Muscle ◽

Adipose Tissue ◽

Energy Expenditure ◽

Oxygen Uptake ◽

Glucose Uptake ◽

Subcutaneous Adipose Tissue ◽

Whole Body ◽

Epinephrine Infusion ◽

Basal Period ◽

Subcutaneous Adipose

Whole body energy expenditure, thermogenic and metabolic changes in the forearm, and intercellular glucose concentrations in subcutaneous adipose tissue on the abdomen determined by microdialysis were measured during epinephrine infusion in healthy subjects. After a control period, epinephrine was infused at rates of 0.2 and 0.4 nmol.kg-1 x min-1. Whole body resting energy expenditure was 4.36 +/- 0.56 (SD) kJ/min. Energy expenditure increased to 5.14 +/- 0.74 and 5.46 +/- 0.79 kJ/min, respectively (P < 0.001), during the epinephrine infusions. Respiratory exchange ratio was 0.80 +/- 0.04 in the resting state and did not change. Local forearm oxygen uptake was 3.9 +/- 1.3 mumol.100 g-1 x min-1 in the basal period. During epinephrine infusion, it increased to 5.8 +/- 2.1 (P < 0.03) and 7.5 +/- 2.3 mumol.100 g-1 x min-1 (P < 0.001). Local forearm glucose uptake was 0.160 +/- 0.105 mumol.100 g-1 x min-1 and increased to 0.586 +/- 0.445 and 0.760 +/- 0.534 mumol.100 g-1 x min-1 (P < 0.025). The intercellular glucose concentration in the subcutaneous adipose tissue on the abdomen was equal to the arterial concentration in the basal period but did not increase as much during infusion of epinephrine, indicating glucose uptake in adipose tissue in this condition. If it is assumed that forearm skeletal muscle is representative for the average skeletal muscle, it can be calculated that on average 40% of the enhanced whole body oxygen uptake induced by infusion of epinephrine is taking place in skeletal muscle. It is proposed that adipose tissue may contribute to epinephrine-induced thermogenesis.

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