Role of CRTC2 in Metabolic Homeostasis: Key Regulator of Whole-Body Energy Metabolism?

Obesity is becoming a pandemic, and its prevalence is still increasing. Considering that obesity increases the risk of developing cardiometabolic diseases, research efforts are focusing on new ways to combat obesity. Brown adipose tissue (BAT) has emerged as a possible target to achieve this for its functional role in energy expenditure by means of increasing thermogenesis. An important metabolic sensor and regulator of whole-body energy balance is AMP-activated protein kinase (AMPK), and its role in energy metabolism is evident. This review highlights the mechanisms of BAT activation and investigates how AMPK can be used as a target for BAT activation. We review compounds and other factors that are able to activate AMPK and further discuss the therapeutic use of AMPK in BAT activation. Extensive research shows that AMPK can be activated by a number of different kinases, such as LKB1, CaMKK, but also small molecules, hormones, and metabolic stresses. AMPK is able to activate BAT by inducing adipogenesis, maintaining mitochondrial homeostasis and inducing browning in white adipose tissue. We conclude that, despite encouraging results, many uncertainties should be clarified before AMPK can be posed as a target for anti-obesity treatment via BAT activation.

Download Full-text

Role of AMPK in mammals reproduction: Specific controls and whole-body energy sensing

Comptes Rendus Biologies ◽

10.1016/j.crvi.2018.10.003 ◽

2019 ◽

Vol 342 (1-2) ◽

pp. 1-6 ◽

Cited By ~ 3

Author(s):

Thi Mong Diep Nguyen

Keyword(s):

Whole Body ◽

Energy Sensing ◽

Body Energy

Download Full-text

Hepatic Crtc2 controls whole body energy metabolism via a miR-34a-Fgf21 axis

Nature Communications ◽

10.1038/s41467-017-01878-6 ◽

2017 ◽

Vol 8 (1) ◽

Cited By ~ 19

Author(s):

Hye-Sook Han ◽

Byeong Hun Choi ◽

Jun Seok Kim ◽

Geon Kang ◽

Seung-Hoi Koo

Keyword(s):

Energy Metabolism ◽

Whole Body ◽

Body Energy

Download Full-text

Resting Whole Body Energy Metabolism in Class 3 Obesity; from Preserved Insulin Sensitivity to Overt Type 2 Diabetes

Diabetes Metabolic Syndrome and Obesity Targets and Therapy ◽

10.2147/dmso.s228229 ◽

2020 ◽

Vol Volume 13 ◽

pp. 489-497 ◽

Cited By ~ 1

Author(s):

Giuseppina Manzoni ◽

Alice Oltolini ◽

Silvia Perra ◽

Emanuele Muraca ◽

Stefano Ciardullo ◽

...

Keyword(s):

Type 2 Diabetes ◽

Insulin Sensitivity ◽

Energy Metabolism ◽

Whole Body ◽

Body Energy

Download Full-text

Uncoupling of sarcoendoplasmic reticulum calcium ATPase pump activity by sarcolipin as the basis for muscle non-shivering thermogenesis

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2019.0135 ◽

2020 ◽

Vol 375 (1793) ◽

pp. 20190135 ◽

Cited By ~ 3

Author(s):

Naresh C. Bal ◽

Muthu Periasamy

Keyword(s):

Energy Homeostasis ◽

Atp Hydrolysis ◽

Calcium Atpase ◽

Whole Body ◽

Signalling Molecule ◽

Brown Adipose ◽

Pump Activity ◽

Body Energy ◽

Shivering Thermogenesis

Thermogenesis in endotherms relies on both shivering and non-shivering thermogenesis (NST). The role of brown adipose tissue (BAT) in NST is well recognized, but the role of muscle-based NST has been contested. However, recent studies have provided substantial evidence for the importance of muscle-based NST in mammals. This review focuses primarily on the role of sarcoplasmic reticulum (SR) Ca 2+ -cycling in muscle NST; specifically, it will discuss recent data showing how uncoupling of sarcoendoplasmic reticulum calcium ATPase (SERCA) (inhibition of Ca 2+ transport but not ATP hydrolysis) by sarcolipin (SLN) results in futile SERCA pump activity, increased ATP hydrolysis and heat production contributing to muscle NST. It will also critically examine how activation of muscle NST can be an important factor in regulating metabolic rate and whole-body energy homeostasis. In this regard, SLN has emerged as a powerful signalling molecule to promote mitochondrial biogenesis and oxidative metabolism in muscle. Furthermore, we will discuss the functional interplay between BAT and muscle, especially with respect to how reduced BAT function in mammals could be compensated by muscle-based NST. Based on the existing data, we argue that SLN-mediated thermogenesis is an integral part of muscle NST and that muscle NST potentially contributed to the evolution of endothermy within the vertebrate clade. This article is part of the theme issue ‘Vertebrate palaeophysiology’.

Download Full-text

TLR4-interactor with leucine-rich repeats (TRIL) is involved in diet-induced hypothalamic inflammation

Scientific Reports ◽

10.1038/s41598-021-97291-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Alexandre Moura-Assis ◽

Pedro A. S. Nogueira ◽

Jose C. de-Lima-Junior ◽

Fernando M. Simabuco ◽

Joana M. Gaspar ◽

...

Keyword(s):

Dietary Fats ◽

Whole Body ◽

Metabolic Dysfunction ◽

Diet Induced Obesity ◽

Hypothalamic Inflammation ◽

Novel Target ◽

Tlr4 Activation ◽

Leucine Rich Repeats ◽

Body Energy

AbstractObesity and high-fat diet (HFD) consumption result in hypothalamic inflammation and metabolic dysfunction. While the TLR4 activation by dietary fats is a well-characterized pathway involved in the neuronal and glial inflammation, the role of its accessory proteins in diet-induced hypothalamic inflammation remains unknown. Here, we demonstrate that the knockdown of TLR4-interactor with leucine-rich repeats (Tril), a functional component of TLR4, resulted in reduced hypothalamic inflammation, increased whole-body energy expenditure, improved the systemic glucose tolerance and protection from diet-induced obesity. The POMC-specific knockdown of Tril resulted in decreased body fat, decreased white adipose tissue inflammation and a trend toward increased leptin signaling in POMC neurons. Thus, Tril was identified as a new component of the complex mechanisms that promote hypothalamic dysfunction in experimental obesity and its inhibition in the hypothalamus may represent a novel target for obesity treatment.

Download Full-text

Adipose tissue NAD+ biosynthesis is required for regulating adaptive thermogenesis and whole-body energy homeostasis in mice

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1909917116 ◽

2019 ◽

Vol 116 (47) ◽

pp. 23822-23828 ◽

Cited By ~ 8

Author(s):

Shintaro Yamaguchi ◽

Michael P. Franczyk ◽

Maria Chondronikola ◽

Nathan Qi ◽

Subhadra C. Gunawardana ◽

...

Keyword(s):

Adipose Tissue ◽

Energy Metabolism ◽

Cold Exposure ◽

Energy Homeostasis ◽

Lipolytic Activity ◽

Whole Body ◽

Brown Adipocyte ◽

Nicotinamide Phosphoribosyltransferase ◽

Adaptive Thermogenesis ◽

Body Energy

Nicotinamide adenine dinucleotide (NAD+) is a critical coenzyme for cellular energy metabolism. The aim of the present study was to determine the importance of brown and white adipose tissue (BAT and WAT) NAD+ metabolism in regulating whole-body thermogenesis and energy metabolism. Accordingly, we generated and analyzed adipocyte-specific nicotinamide phosphoribosyltransferase (Nampt) knockout (ANKO) and brown adipocyte-specific Nampt knockout (BANKO) mice because NAMPT is the rate-limiting NAD+ biosynthetic enzyme. We found ANKO mice, which lack NAMPT in both BAT and WAT, had impaired gene programs involved in thermogenesis and mitochondrial function in BAT and a blunted thermogenic (rectal temperature, BAT temperature, and whole-body oxygen consumption) response to acute cold exposure, prolonged fasting, and administration of β-adrenergic agonists (norepinephrine and CL-316243). In addition, the absence of NAMPT in WAT markedly reduced adrenergic-mediated lipolytic activity, likely through inactivation of the NAD+–SIRT1–caveolin-1 axis, which limits an important fuel source fatty acid for BAT thermogenesis. These metabolic abnormalities were rescued by treatment with nicotinamide mononucleotide (NMN), which bypasses the block in NAD+ synthesis induced by NAMPT deficiency. Although BANKO mice, which lack NAMPT in BAT only, had BAT cellular alterations similar to the ANKO mice, BANKO mice had normal thermogenic and lipolytic responses. We also found NAMPT expression in supraclavicular adipose tissue (where human BAT is localized) obtained from human subjects increased during cold exposure, suggesting our finding in rodents could apply to people. These results demonstrate that adipose NAMPT-mediated NAD+ biosynthesis is essential for regulating adaptive thermogenesis, lipolysis, and whole-body energy metabolism.

Download Full-text