Thyroid hormone triiodothyronine T and its precursor

Thyroid hormone 3,5,3′-triiodothyronine (T3) and its precursor, thyroxine (T4), are iodinated compounds, which are known to regulate the expression of genes involved in various biological processes, such as development, growth and metabolic control. The iodothyronine deiodinase types I, II and III (D1, D2 and D3 respectively) regulate the activity of thyroid hormone via removal of specific iodine moieties from the precursor T4 molecule. Type II enzyme (D2) is mainly responsible for deiodination of T4, thereby generating the active form of thyroid hormone T3, which is implicated in controlling the thermogenesis in mammals [31]. BAT is the major site of adaptive thermogenesis in rodents, with heat being generated as a result of the actions of uncoupling protein 1(UCP-1) [32]. D2 and TGR5 are co-expressed in mouse BAT, which has the highest relative expression level of both genes. The increased expression and activity of D2 in BAT in mice fed on a high fat diet with bile acids confers the resistance offered by bile acids to diet-induced obesity [28]. In contrast to rodents, adult humans do not have significant amount of BAT and utilize skeletal muscle as the component of crucial importance to energy homeostasis. Human skeletal muscle expresses both D2 and TGR5 and bile acids have been reported to increase D2 expression, D2 activity and energy expenditure by means of TGR5 cAMP-mediated pathway (Figure 2) [28]. This would also be more important in maintaining energy homeostasis by bile acids or TGR5 agonists, particularly in adult human subjects carrying BAT in the neck and paravertebral regions [33] and in subjects with increased BAT under high catecholamine states [34] than was once thought. Taken together, all information, in addition to the recent information that adult human skeletal muscles expressing physiologically relevant UCP-1 serve as progenitors of BAT cells [35], indicate that TGR5 agonists should induce thermogenesis, regulating energy expenditure in obese human subjects. It would be however interesting to observe the effects of TGR5 agonists in terms of thermogenesis and energy homeostasis in both healthy and obese populations over a period of time. The bile acid-TGR5-cAMP-D2-T3 pathway could be therapeutically significant in the management of obesity, through the control of thermogenesis and food intake (Figure 3). Human obesity is associated with altered cholesterol homeostasis including increased production and turnover 36, 37 and secretion of excess cholesterol from the liver into bile [38] thereby making a highly saturated bile and, though not proven, could be a possible reason for low energy expenditure in such individuals [39]. Interestingly, the low bile AZD6482 australia synthesis in familial hypercholesterolemia patients was previously regarded as a risk factor for coronary heart disease [40]. Bile acid levels increase in the liver following a meal and a significant amount of bile acid is secreted into the systemic circulation. The postprandial serum levels of bile acids increase up to 15μM, consistent with the pharmacological concentration required to stimulate TGR5 and D2 [41]. Serum bile acid levels could serve as a hormonal signal for food intake and also as a key factor in diet-induced thermogenesis. The induction of thermogenesis by bile acids under insulin resistant state, however, is not known. With the highest association of insulin resistance with obesity, it would be really interesting and worthwhile to study the effects of bile acids and TGR5 agonists in increasing thermogenesis in such subjects.
TGR5 and glucose homeostasis The induction of GLP-1 secretion by bile acids through TGR5 in an enteroendocrine cell line (STC-1) [42] aroused the interest of the pharmaceutical industry in exploring this particular target for the potential treatment of type 2 diabetes through the management of glucose homeostasis. The hypothesis was strengthened by a recent finding with oleanolic acid, a natural TGR5 agonist isolated from olive leaves (O. europaea) that decreased plasma glucose and insulin levels in C57BL/6J mice maintained on a high fat diet for 10 weeks before the start of the 7 days treatment with oleanolic acid [43]. Oleanolic acid improved metabolic homeostasis in high fat-fed mice and partially corrected glucose tolerance in an intraperitoneal glucose tolerance test (IPGTT). The anti-hyperglycemic activity of oleanolic acid, which is a highly specific and potent TGR5 agonist, supports the potential value of targeting TGR5 in type 2 diabetes. Similarly, the expression of TGR5 in the small intestine and other areas of gut [19], coupled with the secretion of GLP-1 in enteroendocrine cells, indicates the therapeutic relevance of TGR5 agonists in the potential treatment of type 2 diabetes. Endocrine L-cells are present throughout the small and large intestine, with the majority localized to the distal ileum and colon [44], where the primary bile acids, such as cholic acid, are converted to the secondary bile acids such as deoxycholic acid, by gut microorganisms [45]. Since secondary bile acids, are more potent at TGR5 than primary acids 18, 19, it possibly implicates TGR5 in the release of GLP-1 in the gut. Given the importance of various activities exhibited by GLP-1 in terms of regulating glucose homeostasis through stimulation of glucose dependent insulin secretion and inhibiting glucagon secretion in the pancreas; inhibition of gastric emptying; increased satiety through neuroendocrine centers thereby reducing food intake, the TGR5 receptor may represent a promising emerging target in the therapeutic management of type 2 diabetes and obesity (Figure 3). To investigate the correlation between TGR5 activation and glucose homeostasis, and to evaluate the therapeutic potential of TGR5 as a target to stimulate GLP-1 secretion, knockout studies (siRNA/shRNA at cellular level or TGR5−/− homozygous mice at in vivo level) may prove to be useful tools.