scholarly journals Protein kinase A induces UCP1 expression in specific adipose depots to increase energy expenditure and improve metabolic health

2016 ◽  
Vol 311 (1) ◽  
pp. R79-R88 ◽  
Author(s):  
Lorna M. Dickson ◽  
Shriya Gandhi ◽  
Brian T. Layden ◽  
Ronald N. Cohen ◽  
Barton Wicksteed
Keyword(s):  
Adipose Tissue ◽  
Energy Expenditure ◽  
Cell Function ◽  
Uncoupling Protein ◽  
Metabolic Health ◽  
Regulatory Subunit ◽  
Increase Energy Expenditure ◽  
Brown Adipose ◽  
Β Cell Function ◽  
Pka Regulatory Subunit

Adipose tissue PKA has roles in adipogenesis, lipolysis, and mitochondrial function. PKA transduces the cAMP signal downstream of G protein-coupled receptors, which are being explored for therapeutic manipulation to reduce obesity and improve metabolic health. This study aimed to determine the overall physiological consequences of PKA activation in adipose tissue. Mice expressing an activated PKA catalytic subunit in adipose tissue (Adipoq-caPKA mice) showed increased PKA activity in subcutaneous, epididymal, and mesenteric white adipose tissue (WAT) depots and brown adipose tissue (BAT) compared with controls. Adipoq-caPKA mice weaned onto a high-fat diet (HFD) or switched to the HFD at 26 wk of age were protected from diet-induced weight gain. Metabolic health was improved, with enhanced insulin sensitivity, glucose tolerance, and β-cell function. Adipose tissue health was improved, with smaller adipocyte size and reduced macrophage engulfment of adipocytes. Using metabolic cages, we found that Adipoq-caPKA mice were shown to have increased energy expenditure, but no difference to littermate controls in physical activity or food consumption. Immunoblotting of adipose tissue showed increased expression of uncoupling protein-1 (UCP1) in BAT and dramatic UCP1 induction in subcutaneous WAT, but no induction in the visceral depots. Feeding a HFD increased PKA activity in epididymal WAT of wild-type mice compared with chow, but did not change PKA activity in subcutaneous WAT or BAT. This was associated with changes in PKA regulatory subunit expression. This study shows that adipose tissue PKA activity is sufficient to increase energy expenditure and indicates that PKA is a beneficial target in metabolic health.

scholarly journals Nutritional Regulation of Human Brown Adipose Tissue

Nutrients ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1748
Author(s):  
Karla J. Suchacki ◽  
Roland H. Stimson
Keyword(s):  
Metabolic Disease ◽  
Adipose Tissue ◽  
Energy Expenditure ◽  
Brown Adipose Tissue ◽  
Therapeutic Potential ◽  
Metabolic Health ◽  
Nutritional Regulation ◽  
Increase Energy Expenditure ◽  
Brown Adipose ◽  
The Impact

The recent identification of brown adipose tissue in adult humans offers a new strategy to increase energy expenditure to treat obesity and associated metabolic disease. While white adipose tissue (WAT) is primarily for energy storage, brown adipose tissue (BAT) is a thermogenic organ that increases energy expenditure to generate heat. BAT is activated upon cold exposure and improves insulin sensitivity and lipid clearance, highlighting its beneficial role in metabolic health in humans. This review provides an overview of BAT physiology in conditions of overnutrition (obesity and associated metabolic disease), undernutrition and in conditions of altered fat distribution such as lipodystrophy. We review the impact of exercise, dietary macronutrients and bioactive compounds on BAT activity. Finally, we discuss the therapeutic potential of dietary manipulations or supplementation to increase energy expenditure and BAT thermogenesis. We conclude that chronic nutritional interventions may represent a useful nonpharmacological means to enhance BAT mass and activity to aid weight loss and/or improve metabolic health.

scholarly journals Human Brown Adipose Tissue and Metabolic Health: Potential for Therapeutic Avenues

2021 ◽  
Author(s):  
Rajan Singh ◽  
Albert Barrios ◽  
Golnaz Dirakvand ◽  
Shehla Pervin
Keyword(s):  
Adipose Tissue ◽  
Energy Expenditure ◽  
Brown Adipose Tissue ◽  
Body Fat ◽  
Metabolic Diseases ◽  
Metabolic Health ◽  
Increase Energy Expenditure ◽  
Brown Adipose ◽  
Adult Humans ◽  
Treatment Of Obesity

Obesity-associated metabolic abnormalities comprise of a cluster of conditions including dyslipidemia, insulin resistance, diabetes, and cardiovascular diseases that has affected more than 650 million people all over the globe. Obesity results from accumulation of white adipose tissues mainly due to the chronic imbalance of energy intake and energy expenditure. Variety of approaches to treat or prevent obesity, including lifestyle interventions, surgical weight loss procedures and pharmacological approaches to reduce energy intake and increase energy expenditure have failed to substantially decrease the prevalence of obesity. Brown adipose tissue (BAT), the primary source of thermogenesis in infants and small mammals may represent a promising therapeutic target to treat obesity by promoting energy expenditure through non-shivering thermogenesis mediated by mitochondrial uncoupling protein 1 (UCP1). Since the confirmation of functional BAT in adult humans by several groups, approximately a decade ago and its association with a favorable metabolic phenotype, intense interest on the significance of BAT in adult human physiology and metabolic health has emerged within the scientific community to explore its therapeutic potential for the treatment of obesity and metabolic diseases. Substantially decreased BAT activity in individuals with obesity indicates a role for BAT in setting of human obesity. On the other hand, BAT mass and its prevalence has been reported to correlate with lower body mass index (BMI), decreased age and glucose levels, leading to lower incidence of cardio metabolic diseases. Increased cold exposure in adult humans with undetectable BAT was associated with decreased body fat mass and increased insulin sensitivity. Deeper understanding of the role of BAT in human metabolic health and its inter-relationship with body fat distribution and deciphering proper strategies to increase energy expenditure by either increasing functional BAT mass, or inducing white adipose browning holds the promise for possible therapeutic avenues for the treatment of obesity and associated metabolic disorders.

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

2004 ◽  
Vol 18 (9) ◽  
pp. 2302-2311 ◽  
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.

scholarly journals Liver X receptor β controls thyroid hormone feedback in the brain and regulates browning of subcutaneous white adipose tissue

2015 ◽  
Vol 112 (45) ◽  
pp. 14006-14011 ◽  
Author(s):  
Yifei Miao ◽  
Wanfu Wu ◽  
Yubing Dai ◽  
Laure Maneix ◽  
Bo Huang ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Thyroid Hormone ◽  
Energy Expenditure ◽  
White Adipose Tissue ◽  
Uncoupling Protein ◽  
Thyroid Stimulating Hormone ◽  
Vital Role ◽  
Normal Diet ◽  
Subcutaneous White Adipose Tissue ◽  
Brown Adipose

The recent discovery of browning of white adipose tissue (WAT) has raised great research interest because of its significant potential in counteracting obesity and type 2 diabetes. Browning is the result of the induction in WAT of a newly discovered type of adipocyte, the beige cell. When mice are exposed to cold or several kinds of hormones or treatments with chemicals, specific depots of WAT undergo a browning process, characterized by highly activated mitochondria and increased heat production and energy expenditure. However, the mechanisms underlying browning are still poorly understood. Liver X receptors (LXRs) are one class of nuclear receptors, which play a vital role in regulating cholesterol, triglyceride, and glucose metabolism. Following our previous finding that LXRs serve as repressors of uncoupling protein-1 (UCP1) in classic brown adipose tissue in female mice, we found that LXRs, especially LXRβ, also repress the browning process of subcutaneous adipose tissue (SAT) in male rodents fed a normal diet. Depletion of LXRs activated thyroid-stimulating hormone (TSH)-releasing hormone (TRH)-positive neurons in the paraventricular nucleus area of the hypothalamus and thus stimulated secretion of TSH from the pituitary. Consequently, production of thyroid hormones in the thyroid gland and circulating thyroid hormone level were increased. Moreover, the activity of thyroid signaling in SAT was markedly increased. Together, our findings have uncovered the basis of increased energy expenditure in male LXR knockout mice and provided support for targeting LXRs in treatment of obesity.

scholarly journals Possible involvement of uncoupling protein 1 in appetite control by leptin

2011 ◽  
Vol 236 (11) ◽  
pp. 1274-1281 ◽  
Author(s):  
Yuko Okamatsu-Ogura ◽  
Junko Nio-Kobayashi ◽  
Toshihiko Iwanaga ◽  
Akira Terao ◽  
Kazuhiro Kimura ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Food Intake ◽  
Energy Expenditure ◽  
Single Injection ◽  
Uncoupling Protein ◽  
Day Treatment ◽  
Repeated Injection ◽  
Appetite Control ◽  
Brown Adipose ◽  
Anorexigenic Effect

Leptin reduces body fat by decreasing food intake and increasing energy expenditure. Uncoupling protein (UCP) 1, a key molecule for brown adipose tissue (BAT) thermogenesis, was reported to contribute to the stimulatory effect of leptin on energy expenditure. To clarify whether UCP1 is also involved in the anorexigenic effect of leptin, in this study we examined the effect of leptin on food intake using wild-type (WT) and UCP1-deficient (UCP1-KO) mice. Repeated injection of leptin decreased food intake more markedly in WT mice than in UCP1-KO mice, while a single injection of leptin showed similar effects in the two groups of mice. As chronic leptin stimulation induces UCP1 expression in BAT and ectopically in white adipose tissue (WAT), we mimicked the UCP1 induction by repeated injection of CL316,243 (CL), a highly specific β3-adrenoceptor agonist, and measured food intake in response to a single injection of leptin. Two-week treatment with CL enhanced the anorexigenic effect of leptin in WT mice, but not in UCP1-KO mice. Three-day treatment with CL in WT mice also enhanced the anorexigenic effect of leptin and leptin-induced phosphorylation of signal transducer and activator of transcription 3 (STAT3) in the arcuate nucleus of the hypothalamus, without any notable change in adiposity. These results indicate that UCP1 enhances leptin action at the hypothalamus level, suggesting UCP1 contributes to the control of energy balance not only through the regulation of energy expenditure but also through appetite control by modulating leptin action.

scholarly journals Brown Adipose Tissue and Its Role in Insulin and Glucose Homeostasis

2021 ◽  
Vol 22 (4) ◽  
pp. 1530
Author(s):  
Katarzyna Maliszewska ◽  
Adam Kretowski
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Energy Expenditure ◽  
Brown Adipose Tissue ◽  
Glucose Homeostasis ◽  
Uncoupling Protein ◽  
Negative Energy ◽  
Metabolic Complications ◽  
Brown Adipose ◽  
Prevalence Of Obesity

The increased worldwide prevalence of obesity, insulin resistance, and their related metabolic complications have prompted the scientific world to search for new possibilities to combat obesity. Brown adipose tissue (BAT), due to its unique protein uncoupling protein 1 (UPC1) in the inner membrane of the mitochondria, has been acknowledged as a promising approach to increase energy expenditure. Activated brown adipocytes dissipate energy, resulting in heat production. In other words, BAT burns fat and increases the metabolic rate, promoting a negative energy balance. Moreover, BAT alleviates metabolic complications like dyslipidemia, impaired insulin secretion, and insulin resistance in type 2 diabetes. The aim of this review is to explore the role of BAT in total energy expenditure, as well as lipid and glucose homeostasis, and to discuss new possible activators of brown adipose tissue in humans to treat obesity and metabolic disorders.

scholarly journals Brown adipose tissue, energy expenditure, and biomarkers of cardio-metabolic health among the Yakut (Sakha) of northeastern Siberia

2018 ◽  
Vol 30 (6) ◽  
pp. e23175 ◽  
Author(s):  
Stephanie B. Levy ◽  
Tatiana M. Klimova ◽  
Raisa N. Zakharova ◽  
Afanasiy I. Federov ◽  
Valentina I. Fedorova ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Energy Expenditure ◽  
Brown Adipose Tissue ◽  
Metabolic Health ◽  
Northeastern Siberia ◽  
Brown Adipose

scholarly journals FTO Deficiency Induces UCP-1 Expression and Mitochondrial Uncoupling in Adipocytes

Endocrinology ◽  
2013 ◽  
Vol 154 (9) ◽  
pp. 3141-3151 ◽  
Author(s):  
D. Tews ◽  
P. Fischer-Posovszky ◽  
T. Fromme ◽  
M. Klingenspor ◽  
J. Fischer ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Energy Expenditure ◽  
Fat Mass ◽  
Uncoupling Protein ◽  
Association Studies ◽  
De Novo Lipogenesis ◽  
Brown Adipocyte ◽  
Genome Wide Association Studies ◽  
Mitochondrial Uncoupling ◽  
Brown Adipose

Variants in the fat mass- and obesity-associated (FTO) gene are associated with obesity and body fat mass in genome-wide association studies. However, the mechanism by which FTO predisposes individuals to obesity is not clear so far. First mechanistic evidence was shown in Fto-negative mice. These mice are resistant to obesity due to enhanced energy expenditure, whereas the mass of brown adipose tissue remains unchanged. We hypothesize that FTO is involved in the induction of white adipose tissue browning, which leads to mitochondrial uncoupling and increases energy expenditure. Uncoupling protein 1 (Ucp-1) was significantly higher expressed in both gonadal and inguinal adipose depots of Fto−/− compared with Fto+/+ littermates accompanied by the appearance of multivacuolar, Ucp-1-positive adipocytes in these tissues. By using lentiviral short hairpin RNA constructs, we established FTO-deficient human preadipocytes and adipocytes and analyzed key metabolic processes. FTO-deficient adipocytes showed an adipogenic differentiation rate comparable with control cells but exhibited a reduced de novo lipogenesis despite unchanged glucose uptake. In agreement with the mouse data, FTO-deficient adipocytes exhibited 4-fold higher expression of UCP-1 in mitochondria compared with control cells. The up-regulation of UCP-1 in FTO-deficient adipocytes resulted in enhanced mitochondrial uncoupling. We conclude that FTO deficiency leads to the induction of a brown adipocyte phenotype, thereby enhancing energy expenditure. Further understanding of the signaling pathway connecting FTO with UCP-1 expression might lead to new options for obesity and overweight treatment.

Invited Review: Uncoupling proteins and thermoregulation

2002 ◽  
Vol 92 (5) ◽  
pp. 2187-2198 ◽  
Author(s):  
George Argyropoulos ◽  
Mary-Ellen Harper
Keyword(s):  
Adipose Tissue ◽  
Energy Expenditure ◽  
Uncoupling Protein ◽  
Biochemical Properties ◽  
Atp Production ◽  
Metabolic Functions ◽  
Mitochondrial Inner Membrane ◽  
Brown Adipose ◽  
Total Body ◽  
Body Energy

Energy balance in animals is a metabolic state that exists when total body energy expenditure equals dietary energy intake. Energy expenditure, or thermogenesis, can be subcategorized into groups of obligatory and facultative metabolic processes. Brown adipose tissue (BAT), through the activity of uncoupling protein 1 (UCP1), is responsible for nonshivering thermogenesis, a major component of facultative thermogenesis in newborn humans and in small mammals. UCP1, found in the mitochondrial inner membrane in BAT, uncouples energy substrate oxidation from mitochondrial ATP production and hence results in the loss of potential energy as heat. Mice that do not express UCP1 (UCP1 knockouts) are markedly cold sensitive. The recent identification of four new homologs to UCP1 expressed in BAT, muscle, white adipose tissue, brain, and other tissues has been met by tremendous scientific interest. The hypothesis that the novel UCPs may regulate thermogenesis and/or fatty acid metabolism guides investigations worldwide. Despite several hundred publications on the new UCPs, there are a number of significant controversies, and only a limited understanding of their physiological and biochemical properties has emerged. The discovery of UCP orthologs in fish, birds, insects, and even plants suggests the widespread importance of their metabolic functions. Answers to fundamental questions regarding the metabolic functions of the new UCPs are thus pending and more research is needed to elucidate their physiological functions. In this review, we discuss recent findings from mammalian studies in an effort to identify potential patterns of function for the UCPs.

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