GPR180 is a component of TGFβ signalling that promotes thermogenic adipocyte function and mediates the metabolic effects of the adipocyte-secreted factor CTHRC1

AbstractActivation of thermogenic brown and beige adipocytes is considered as a strategy to improve metabolic control. Here, we identify GPR180 as a receptor regulating brown and beige adipocyte function and whole-body glucose homeostasis, whose expression in humans is associated with improved metabolic control. We demonstrate that GPR180 is not a GPCR but a component of the TGFβ signalling pathway and regulates the activity of the TGFβ receptor complex through SMAD3 phosphorylation. In addition, using genetic and pharmacological tools, we provide evidence that GPR180 is required to manifest Collagen triple helix repeat containing 1 (CTHRC1) action to regulate brown and beige adipocyte activity and glucose homeostasis. In this work, we show that CTHRC1/GPR180 signalling integrates into the TGFβ signalling as an alternative axis to fine-tune and achieve low-grade activation of the pathway to prevent pathophysiological response while contributing to control of glucose and energy metabolism.

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Beige Fat, Adaptive Thermogenesis, and Its Regulation by Exercise and Thyroid Hormone

Biology ◽

10.3390/biology8030057 ◽

2019 ◽

Vol 8 (3) ◽

pp. 57 ◽

Cited By ~ 6

Author(s):

Kevin J. Phillips

Keyword(s):

Adipose Tissue ◽

Thyroid Hormone ◽

Metabolic Effects ◽

Adipose Tissues ◽

Beige Adipocyte ◽

Adaptive Thermogenesis ◽

Beige Adipocytes ◽

Beige Fat ◽

Beige Cells ◽

Adipocyte Development

While it is now understood that the proper expansion of adipose tissue is critically important for metabolic homeostasis, it is also appreciated that adipose tissues perform far more functions than simply maintaining energy balance. Adipose tissue performs endocrine functions, secreting hormones or adipokines that affect the regulation of extra-adipose tissues, and, under certain conditions, can also be major contributors to energy expenditure and the systemic metabolic rate via the activation of thermogenesis. Adipose thermogenesis takes place in brown and beige adipocytes. While brown adipocytes have been relatively well studied, the study of beige adipocytes has only recently become an area of considerable exploration. Numerous suggestions have been made that beige adipocytes can elicit beneficial metabolic effects on body weight, insulin sensitivity, and lipid levels. However, the potential impact of beige adipocyte thermogenesis on systemic metabolism is not yet clear and an understanding of beige adipocyte development and regulation is also limited. This review will highlight our current understanding of beige adipocytes and select factors that have been reported to elicit the development and activation of thermogenesis in beige cells, with a focus on factors that may represent a link between exercise and ‘beiging’, as well as the role that thyroid hormone signaling plays in beige adipocyte regulation.

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Role of toll-like receptors and their ligands in adipocyte secretion

Annals of Proteomics and Bioinformatics ◽

10.29328/journal.apb.1001012 ◽

2021 ◽

Vol 5 (1) ◽

pp. 001-007

Author(s):

Mishra A ◽

Shestopalov AV ◽

Gaponov AM ◽

Alexandrov IA ◽

Roumiantsev SA

Keyword(s):

Adipose Tissue ◽

Energy Homeostasis ◽

Whole Body ◽

Low Grade ◽

White Adipocyte ◽

White Adipocytes ◽

Beige Adipocytes ◽

Whole Body Metabolism ◽

Significant Expression ◽

Adipose Tissue Remodeling

Background: Adipose tissue is one of the main sites of energy homeostasis that regulates whole body metabolism with the help of adipokines. Disruption in its proper functioning results in adipose tissue remodeling (primarily hypertrophy and hyperplasia) which directly influences the secretion of said adipokines. Obesity characterized as chronic low-grade inflammation of the adipose tissue is one such condition that has far reaching effects on whole body metabolism. Inflammation in turn results in immune cells infiltrating into the tissue and further promoting adipocyte dysfunction. Purpose: In our study we explored this adipose tissue-innate immunity axis by differentiating adipose tissue derived stem cells (ADSCs) into white and beige adipocytes. We further stimulated our cultures with lipopolysaccharide (LPS), flagellin, or meteorin-like, glial cell differentiation regulator (METRNL) to trigger an inflammatory response. We then evaluated Toll-like receptor (TLR) mRNA expression and secretion of interleukin (IL-6), interleukin-8 (IL-8), brain-derived neurotrophic factor (BDNF), and nerve growth factor (NGF) in these cultures. Results: We found that TLR2 is the highest expressed receptor in adipocytes. Further, LPS and METRNL are strong activators of TLR2 in white and beigeBMP7(-) adipocytes. TLR4 was not significantly expressed in any of our cultures despite LPS stimulation. TLR9 expression is upregulated in ADSCs upon LPS and METRNL stimulation. IL-6 and IL-8 secretion is increased upon LPS stimulation in white adipocytes. METRNL activates both IL-6 and IL-8 expression in adipocyte cultures. Lastly, BDNF and NGF is secreted by all adipocyte cultures with beigeBMP7(-) and beigeBMP7(+) secreting slightly higher amounts in comparison to white adipocytes. Conclusion: ADSCs and adipocytes alike are capable of expressing TLRs, but white adipocytes remain the highest expressing in both control and stimulated cultures. TLR2 is highly expressed in white and beige adipocytes whereas TLR4 showed no significant expression. LPS and METRNL trigger IL-6 and IL-8 secretion in adipocytes. Products of white adipocyte “browning” are capable of secreting higher amounts of BDNF and NGF in comparison to white adipocytes.

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Critical review of beige adipocyte thermogenic activation and contribution to whole-body energy expenditure

Hormone Molecular Biology and Clinical Investigation ◽

10.1515/hmbci-2017-0042 ◽

2017 ◽

Vol 31 (2) ◽

Cited By ~ 8

Author(s):

Érique Castro ◽

Tiago E. Oliveira Silva ◽

William T. Festuccia

Keyword(s):

Energy Expenditure ◽

Metabolic Diseases ◽

Uncoupling Protein ◽

Whole Body ◽

Beige Adipocyte ◽

White Adipocytes ◽

Beige Adipocytes ◽

Whole Body Metabolism ◽

Beige Cells ◽

Body Energy

AbstractBeige (or brite, “brown in white”) adipocytes are uncoupling protein 1 (UCP1)-positive cells residing in white adipose depots that, depending on the conditions, behave either as classic white adipocytes, storing energy as lipids, or as brown adipocytes, dissipating energy from oxidative metabolism as heat through non-shivering thermogenesis. Because of their thermogenic potential and, therefore, possible usage to treat metabolic diseases such as obesity and type 2 diabetes, beige cells have attracted the attention of many scientists worldwide aiming to develop strategies to safely recruit and activate their thermogenic activity. Indeed, in recent years, a large variety of conditions, molecules (including nutrients) and signaling pathways were reported to promote the recruitment of beige adipocytes. Despite of those advances, the true contribution of beige adipocyte thermogenesis to whole-body energy expenditure is still not completely defined. Herein, we discuss some important aspects that should be considered when studying beige adipocyte biology and the contribution to energy balance and whole-body metabolism.

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Thermoneutral housing does not influence fat mass or glucose homeostasis in C57BL/6 mice

Journal of Endocrinology ◽

10.1530/joe-18-0279 ◽

2018 ◽

Vol 239 (3) ◽

pp. 313-324 ◽

Cited By ~ 9

Author(s):

Lewin Small ◽

Henry Gong ◽

Christian Yassmin ◽

Gregory J Cooney ◽

Amanda E Brandon

Keyword(s):

Glucose Metabolism ◽

Ambient Temperature ◽

Fat Mass ◽

Glucose Homeostasis ◽

Dietary Intervention ◽

Whole Body ◽

Housing Temperature ◽

Brown Adipose ◽

Normal Chow ◽

Obesogenic Diet

One major factor affecting physiology often overlooked when comparing data from animal models and humans is the effect of ambient temperature. The majority of rodent housing is maintained at ~22°C, the thermoneutral temperature for lightly clothed humans. However, mice have a much higher thermoneutral temperature of ~30°C, consequently data collected at 22°C in mice could be influenced by animals being exposed to a chronic cold stress. The aim of this study was to investigate the effect of housing temperature on glucose homeostasis and energy metabolism of mice fed normal chow or a high-fat, obesogenic diet (HFD). Male C57BL/6J(Arc) mice were housed at standard temperature (22°C) or at thermoneutrality (29°C) and fed either chow or a 60% HFD for 13 weeks. The HFD increased fat mass and produced glucose intolerance as expected but this was not exacerbated in mice housed at thermoneutrality. Changing the ambient temperature, however, did alter energy expenditure, food intake, lipid content and glucose metabolism in skeletal muscle, liver and brown adipose tissue. Collectively, these findings demonstrate that mice regulate energy balance at different housing temperatures to maintain whole-body glucose tolerance and adiposity irrespective of the diet. Despite this, metabolic differences in individual tissues were apparent. In conclusion, dietary intervention in mice has a greater impact on adiposity and glucose metabolism than housing temperature although temperature is still a significant factor in regulating metabolic parameters in individual tissues.

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1971-P: Activation of Adipocyte Gq Signaling Causes Improved Whole-Body Glucose Homeostasis

Diabetes ◽

10.2337/db20-1971-p ◽

2020 ◽

Vol 69 (Supplement 1) ◽

pp. 1971-P

Author(s):

TAKEFUMI KIMURA ◽

SAI PRASAD PYDI ◽

LEI WANG ◽

YINGHONG CUI ◽

OKSANA GAVRILOVA ◽

...

Keyword(s):

Glucose Homeostasis ◽

Whole Body

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Using a simple rope-pulley system that mechanically couples the arms, legs, and treadmill reduces the metabolic cost of walking

Journal of NeuroEngineering and Rehabilitation ◽

10.1186/s12984-021-00887-3 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Daisey Vega ◽

Christopher J. Arellano

Keyword(s):

Metabolic Cost ◽

Metabolic Energy ◽

Metabolic Effects ◽

Whole Body ◽

Walking Ability ◽

Arm Swing ◽

Pulley System ◽

Young Subjects ◽

Walking Recovery ◽

Set Up

Abstract Background Emphasizing the active use of the arms and coordinating them with the stepping motion of the legs may promote walking recovery in patients with impaired lower limb function. Yet, most approaches use seated devices to allow coupled arm and leg movements. To provide an option during treadmill walking, we designed a rope-pulley system that physically links the arms and legs. This arm-leg pulley system was grounded to the floor and made of commercially available slotted square tubing, solid strut channels, and low-friction pulleys that allowed us to use a rope to connect the subject’s wrist to the ipsilateral foot. This set-up was based on our idea that during walking the arm could generate an assistive force during arm swing retraction and, therefore, aid in leg swing. Methods To test this idea, we compared the mechanical, muscular, and metabolic effects between normal walking and walking with the arm-leg pulley system. We measured rope and ground reaction forces, electromyographic signals of key arm and leg muscles, and rates of metabolic energy consumption while healthy, young subjects walked at 1.25 m/s on a dual-belt instrumented treadmill (n = 8). Results With our arm-leg pulley system, we found that an assistive force could be generated, reaching peak values of 7% body weight on average. Contrary to our expectation, the force mainly coincided with the propulsive phase of walking and not leg swing. Our findings suggest that subjects actively used their arms to harness the energy from the moving treadmill belt, which helped to propel the whole body via the arm-leg rope linkage. This effectively decreased the muscular and mechanical demands placed on the legs, reducing the propulsive impulse by 43% (p < 0.001), which led to a 17% net reduction in the metabolic power required for walking (p = 0.001). Conclusions These findings provide the biomechanical and energetic basis for how we might reimagine the use of the arms in gait rehabilitation, opening the opportunity to explore if such a method could help patients regain their walking ability. Trial registration: Study registered on 09/29/2018 in ClinicalTrials.gov (ID—NCT03689647).

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Metabolic Effects of Acute Hyperketonaemia in Man before and during An Hyperinsulinaemic Euglycaemic Clamp

Clinical Science ◽

10.1042/cs0860677 ◽

1994 ◽

Vol 86 (6) ◽

pp. 677-687 ◽

Cited By ~ 14

Author(s):

J. Webber ◽

E. Simpson ◽

H. Parkin ◽

I. A. MacDonald

Keyword(s):

Adipose Tissue ◽

Glucose Uptake ◽

Glucose Oxidation ◽

Respiratory Exchange Ratio ◽

Saline Infusion ◽

Metabolic Effects ◽

Whole Body ◽

Glucose Storage ◽

Adipose Tissue Lipolysis ◽

Subcutaneous Abdominal Adipose Tissue

1. The effects of acutely raising blood ketone body levels to those seen after 72 h of starvation were examined in 10 subjects after an overnight fast. Metabolic rate and respiratory exchange ratio were measured with indirect calorimetry before and during an insulin—glucose clamp. Arteriovenous differences were measured across forearm and subcutaneous abdominal adipose tissue. 2. In response to the clamp the respiratory exchange ratio rose from 0.82 to 0.83 during 3-hydroxybutyrate infusion and from 0.83 to 0.94 during control (saline) infusion (P < 0.001). 3. Forearm glucose uptake at the end of the clamp was 4.02 ± 0.95 (3-hydroxybutyrate infusion) and 7.09 ± 1.24 mmol min−1 100 ml−1 forearm (saline infusion). Whole body glucose uptake at the end of the clamp was 72.8 ± 7.9 (3-hydroxybutyrate infusion) and 51.0 ± 3.0 (saline infusion) mmol min−1 kg−1 body weight−1. 4. 3-Hydroxybutyrate infusion reduced the baseline abdominal venous—arterialized venous glycerol difference from 84 ± 28 to 25 ± 12 mmol/l and the non-esterified fatty acid difference from 0.60 ± 0.17 to 0.02 ± 0.09 mmol/l (P < 0.05 versus saline infusion). 5. Hyperketonaemia reduces adipose tissue lipolysis and decreases insulin-mediated forearm glucose uptake. Hyperketonaemia appears to prevent insulin-stimulated glucose oxidation, but does not reduce insulin-mediated glucose storage.

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p-Coumaric Acid Enhances Hypothalamic Leptin Signaling and Glucose Homeostasis in Mice via Differential Effects on AMPK Activation

International Journal of Molecular Sciences ◽

10.3390/ijms22031431 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1431

Author(s):

Linh V. Nguyen ◽

Khoa D. A. Nguyen ◽

Chi-Thanh Ma ◽

Quoc-Thai Nguyen ◽

Huong T. H. Nguyen ◽

...

Keyword(s):

Glucose Homeostasis ◽

Blood Glucose Control ◽

Whole Body ◽

Ampk Activation ◽

Coumaric Acid ◽

Leptin Signaling ◽

Differential Effects ◽

Leptin Sensitivity ◽

Ampk Activity

AMP-activated protein kinase (AMPK) plays a crucial role in the regulation of energy homeostasis in both peripheral metabolic organs and the central nervous system. Recent studies indicated that p-Coumaric acid (CA), a hydroxycinnamic phenolic acid, potentially activated the peripheral AMPK pathway to exert beneficial effects on glucose metabolism in vitro. However, CA’s actions on central AMPK activity and whole-body glucose homeostasis have not yet been investigated. Here, we reported that CA exhibited different effects on peripheral and central AMPK activation both in vitro and in vivo. Specifically, while CA treatment promoted hepatic AMPK activation, it showed an inhibitory effect on hypothalamic AMPK activity possibly by activating the S6 kinase. Furthermore, CA treatment enhanced hypothalamic leptin sensitivity, resulting in increased proopiomelanocortin (POMC) expression, decreased agouti-related peptide (AgRP) expression, and reduced daily food intake. Overall, CA treatment improved blood glucose control, glucose tolerance, and insulin sensitivity. Together, these results suggested that CA treatment enhanced hypothalamic leptin signaling and whole-body glucose homeostasis, possibly via its differential effects on AMPK activation.

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Lack of Syndecan-1 produces significant alterations in whole-body composition, metabolism and glucose homeostasis in mice

World Journal of Diabetes ◽

10.4239/wjd.v11.i4.126 ◽

2020 ◽

Vol 11 (4) ◽

pp. 126-136

Author(s):

Anil Kumar Jaiswal ◽

Mohanraj Sadasivam ◽

Susan Aja ◽

Abdel Rahim A Hamad

Keyword(s):

Body Composition ◽

Glucose Homeostasis ◽

Whole Body

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An organ-based multi-level model for glucose homeostasis: organ distributions, timing, and impact of blood flow

10.1101/2020.10.21.344499 ◽

2020 ◽

Author(s):

Tilda Herrgårdh ◽

Hao Li ◽

Elin Nyman ◽

Gunnar Cedersund

Keyword(s):

Blood Flow ◽

Glucose Homeostasis ◽

Statistical Tests ◽

Cellular Level ◽

Whole Body ◽

Response Curves ◽

Future Data ◽

Level Model ◽

Multi Level ◽

Original Cell

AbstractGlucose homeostasis is the tight control of glucose in the blood. This complex control is important and not yet sufficiently understood, due to its malfunction in serious diseases like diabetes. Due to the involvement of numerous organs and sub-systems, each with their own intra-cellular control, we have developed a multi-level mathematical model, for glucose homeostasis, which integrates a variety of data. Over the last 10 years, this model has been used to insert new insights from the intra-cellular level into the larger whole-body perspective. However, the original cell-organ-body translation has during these years never been updated, despite several critical shortcomings, which also have not been resolved by other modelling efforts. For this reason, we here present an updated multi-level model. This model provides a more accurate sub-division of how much glucose is being taken up by the different organs. Unlike the original model, we now also account for the different dynamics seen in the different organs. The new model also incorporates the central impact of blood flow on insulin-stimulated glucose uptake. Each new improvement is clear upon visual inspection, and they are also supported by statistical tests. The final multi-level model describes >300 data points in >40 time-series and dose-response curves, resulting from a large variety of perturbations, describing both intra-cellular processes, organ fluxes, and whole-body meal responses. We hope that this model will serve as an improved basis for future data integration, useful for research and drug developments within diabetes.

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