Studies using bone marrow-derived MSC with SIRT1 deletion showed impaired self- renewal and differentiation to osteoblasts without significantly affecting their differentiation to adipocytes [ 54 ]. In the light of these observations it has been suggested that although SIRT1 inhibits adipocyte differentiation, its expression is critical for maintenance of MSC pool [ 11 ]. This suggests that SIRT7 influences adipogenesis in mice by inhibiting autocatalytic activation of SIRT1, further highlighting the importance of cross talk among sirtuins in the control of adipose tissue maintenance [ 38 ].
During times of positive energy balance, storage of lipids as triglycerides in lipid droplets in adipocytes leads to expansion of adipose tissue. It leads to changes in the levels of adipokines such as leptin and adiponectin that affect metabolic functions of other organs particularly liver, muscle and brain, which in turn can affect the adipose tissue function [ 43 , 45 ]. The stored lipid is mobilized in response to hormones and systemic energy needs during periods of negative energy balance.
Metabolism of adipose tissue is thus linked with that of other tissues. SIRT1 appears to serve as an important metabolic switch through which adipose tissue and other metabolic organs respond to energy needs [ 8 ]. When energy stores are high, excess nutrients particularly glucose and amino acids are used to synthesize fatty acids de novo primarily in liver and are exported to WAT where they are stored as TG [ 6 ] SIRT1 deacetylates sterol-responsive element binding protein 1c SREBP1c causing reduction of its transcriptional ability and suppression of fatty acid synthesis [ 6 ].
The hepatic effects of sirtuins can thus affect nutrient flux into the adipose tissue. Activation of SIRT1 reduces expression of acetyl coA carboxylase and other lipogenic genes involved in the de novo synthesis of FAs in pre-adipocytes. Insulin dependent glucose uptake in the adipocyte takes place through the GLUT4 transporter. Deletion of mitochondrial SIRT4 decreased lipogenesis apparently by regulating malonyl CoA decarboxylase, thereby altering the level of malonyl CoA that represses fatty acid oxidation [ 65 , 66 ].
It therefore appears that SIRT4 exhibits a dual effect regulating anabolism and catabolism of fatty acids [ 65 ].
SIRT6 also appears to regulate lipogenesis. During periods of negative energy balance, the triglycerides stored in the lipid droplets, are hydrolysed to FFA which are released into circulation.
WAT can Acquire the Properties of BAT
In the basal state or during TG synthesis, perilipin, the structural protein on lipid droplet, is bound to protein CGI comparative gene identification which is a co-activator of the adipose triglyceride lipase ATGL. Further activation of hormone sensitive lipase HSL by PKA mediated phosphorylation causes binding of HSL to perilipin and continues lipolysis forming monoacyl glycerol which is acted upon by another specific monoacyl glycerol lipase MGL forming glycerol and FFA which are released to plasma for systemic utilization.
In in vivo studies using mice receiving high fat diet, activators of SIRT1 such as resveratrol reduced fat mass [ 69 ]. Further, over expression of SIRT1 inhibited diet induced accumulation of fat [ 6 , 31 , 52 ]. SIRT2 also appears to show similar effect on fat mobilization [ 58 , 59 ]. Although sirtuins influence mitochondrial oxidative metabolism in other metabolic tissues such as liver, their role in WAT mitochondrial metabolism is poorly understood. BMP7 stimulation of progenitor cells leads to down regulation of early adipogenic inhibitors such as Pref1, Nectin, Wnt signaling molecules [ 43 ].
This leads to increased biogenesis of mitochondria. Sirtuins also appear to play a role in the differentiation and function of BAT.
SIRT1 also appears to have a role in differentiation of pre-adipocyte to brown adipocytes. Of the different sirtuins, SIRT3 appeared to be critical in the differentiation of brown adipocytes. Grossly elevated fat stores in adipose tissue with hypertrophic or hyperplastic adipocytes and concomitant development of blood vessels result in obesity. The relevance of sirtuins in adipose tissue development and metabolism and their effects on metabolism of glucose and lipids primarily in the liver, and insulin function suggest a possible link between sirtuins and obesity.
The level of expression and activity of SIRT1 decrease in adipose tissue in different obesity models. SIRT1 expression in obese pigs is reported to be lesser than that in lean pigs [ 82 ]. Apart from decrease in SIRT1 levels, its function is also affected by changes in its post translational modification in obesity.
Advances in the understanding of adipose tissue biology | Nature Reviews Endocrinology
One of the important post-translational modifications of SIRT1 which has been shown to be affected in obesity leading to inhibition of its nuclear localization is casein kinase mediated phosphorylation of ser which is enhanced in obese and not in lean animals [ 83 ]. Unlike SIRT1 which is decreased in WAT in obesity, there is no consensus on the changes in other sirtuins in obese WAT; while some reports show decrease in SIRT2—6, other reports do not show any significant differences between obese and respective controls. It has been shown that mir34a, which regulates the expression and activity of Sirt1, is elevated in obesity [ 41 ].
A possible association of sirtuins with obesity and obesity-associated pathological conditions in humans has also been indicated mostly from observational studies [ 84 , 85 , 86 , 87 , 88 ]. There is significant reduction in sirtuins in adipose tissue and other metabolic tissues in obese subjects and that weight loss or long term fasting can result in increase in their expression. Insulin resistance is a hallmark of obesity and a major factor contributing to obesity associated pathological conditions. In vitro and in vivo studies suggest that SIRT1 regulates insulin response.
SIRT1 regulated insulin-dependent glucose uptake in adipocytes.
Increase in SIRT1 activity improved insulin sensitivity [ 90 ]. Adipose tissue-specific SIRT1 knockout mice were reported to be more prone to developing insulin resistance. In experimentally induced diabetic animals, overexpression of SIRT1 increased insulin sensitivity. Further, SIRT1 deficiency impaired insulin secretion apparently by disrupting glucose sensing and impairing response to fluctuations in glucose levels [ 93 ].
Inflammation of adipose tissue in obesity is a major contributor to insulin resistance and pathogenesis of the metabolic syndrome [ 98 ]. SIRT1 could act as a transcriptional regulator of inflammation in multiple tissues, particularly adipose tissue as well as macrophages and endothelial cells [ 90 , 99 ].
The levels of SIRT1 is inversely related to inflammation in adipose tissue. SIRT1 expression in human subcutaneous adipose tissue was less in cases where macrophage infiltration was high [ , , ]. Activation of C-jun N terminal kinase JNK1 , which is a key component in inflammation associated signaling pathway, leads to phosphorylation of SIRT1, followed by its degradation in proteasomes [ 53 , ].
This suggests that SIRT1 and inflammatory signals interact at various levels and that SIRT1 is an important molecular link between nutrients, inflammation and metabolic dysfunction of the tissue. Since sirtuins play an important role in regulation of adipogenesis, and adipose tissue metabolism, pharmacological activation of sirtuins could be a useful approach for the treatment of obesity and related metabolic disorders.
Sirt1 is an allosteric enzyme which is regulated by ligand binding.
Adipose tissue biology
Resveratrol, which is a naturally occurring polyphenol with anti-oxidant property, increased the enzyme activity of SIRT1 by binding to its allosteric site [ ]. High throughput screening has identified several small molecular activators of SIRT1 [ ]. The most potent of these is SRT which, protects against diet induced obesity [ 6 ]. The administration of SRT reduced expression of lipogenic enzymes and reduced hepatic lipid accumulation, it also enhanced oxidative metabolism in skeletal muscle, liver and BAT in mice, protecting from HFD induced obesity and insulin resistance [ ].
However, increasing sirtuin activity could result in indiscriminate deacetylation of histones and several other key proteins in different tissues. Sirtuin activating therapies would therefore have to be target specific. Epigenetic modifications have emerged as fundamental modulators of metabolic functions, and sirtuins, a group of class III histone deacetylases, play a key role in this context. Related Stories. Beige fat cells, a special type of adipocytes, have the capability to use energy reserves — fatty A new study is the first of its kind to show the effects of eating versus fasting on gene expression in White adipocytes are mainly located in the abdominal and subcutaneous areas of the body and highly adapted to store excess energy.
Conversely, beige But this is no reason to demonize these drugs, the Antimicrobial Resistance Is Drastically Rising. They produced the first global of White, brown, and the more recently identified beige brite phenotypes of adipose tissue may represent a prerequisite for fulfilling the distinct functions.
Therefore, derangements in the adipose tissue regulation, as occurring with excess adiposity, have a broad pathophysiological impact, with the consequences for cardiovascular health being particularly detrimental. Local and systemic effects of obesity-related adipose tissue abnormalities include altered lipid and glucose metabolism, inflammation, endothelial dysfunction, insulin resistance, cardiac and vascular remodeling, fibrosis, hypercoagulability, and cell proliferation.
The cardiovascular implications of ectopic fat and specifically accumulation of visceral, pericardial and perivascular adipose tissue have also been described. As a result, excess adiposity is associated with elevated prevalence and incidence of subclinical risk factors and overt cardiovascular diseases, making obesity the leading contributor to cardiovascular morbidity and mortality worldwide.
By providing contributions from pre-clinical and clinical studies, this Research Topic aims at reviewing current evidence on adipose tissue biology with special emphasis on phenotypes, functions and ramifications for cardiovascular disease risk. The structure and physiology of adipose tissue phenotypes, the pathological role of adipose tissue dysregulation and underlying candidate mechanisms mediating increased cardiovascular risk are examined in a translational manner. Data on the interplay between excess adiposity, body weight regulation, and conventional and novel precursors of cardiovascular disease are also presented.