The use of TRβ
analogs has been shown to have promising metabolic effects in animals fed chow diet (23
) and in animal models of nonalcoholic liver disease (9
) or genetic hypercholesterolemia (10
), with only minimal repercussions in heart (5
), bone (22
), brain (24
), or perturbations of thyroid hormone homeostasis (13
). In this regard, a striking effect of TRβ
-selective agonists is to accelerate the basal metabolic rate with a resulting decrease in adiposity and body weight (11
), as also documented in the present study (). Thus, a logical next step and the scope of the present investigation was (i) to identify the site(s) where TRβ
-selective agonists, for example, GC-24, are acting to produce their metabolic effects, and (ii) whether these effect can be harnessed to prevent obesity in animals kept on a HFD.
On the basis of data obtained with GC-1, another TRβ
-selective agonist, one would expect that BAT be a primary target of GC-24 (13
). In fact, brown adipocytes in culture respond to GC-24 by increasing expression of 11 metabolically relevant genes that were tested (). Further, animals kept on chow diet had their energy expenditure rate accelerated by treatment with GC-24 () without affecting their caloric intake (), limiting their body weight gain over time (). However, in the present mouse model of obesity, expression of a number of BAT genes was not affected at all by treatment with a dose of GC-24 that is the molar equivalent to 10 times the physiological replacement dose of T3 (). Despite this, a small reduction in body weight gain () and sizable modifications in gene expression in the heart of the same animals were observed (). Interestingly, treatment with GC-24 did not affect gene expression in the skeletal muscle of the obese mice (), nor did it in the primary cultures of skeletal myocytes (), making it unlikely that muscle is the site at which TRβ
-selective agonists trigger their main effects. In the liver, a bona fide target of TRβ
-selective agonists (25
), treatment with GC-24 only induced Cyp7a
and lowered Srb1
, whereas expression of other genes remained unaffected (). Although induction of Cyp7a
is compatible with the cholesterol-lowering effect of TRβ
-selective agonists, it is puzzling the lack of a major foot print left by GC-24.
These observations raise two important questions: (i) Is thyroid hormone (or GC-24) signaling reduced in obesity and/or models of high-fat feeding? (ii) What is the mechanism by which treatment with GC-24 prevents body weight gain in the present mouse model of obesity? Addressing the first question, recent studies indicate that thyroid hormone signaling is likely to be impaired in humans with fatty liver, after a large gene set of positively regulated T3-responsive genes was found to be downregulated in surgical liver biopsies from obese subjects (26
). Further, T3-induced expression of this set of genes in the mouse liver was abolished by feeding a HFD, indicating that impaired thyroid hormone action contributes to altered patterns of gene expression in fatty liver. This study supports these recent observations to the extent that the GC-24-induced acceleration of energy expenditure in mice fed a chow diet was diminished in the obese animals ( vs. ), as was the reduction in body weight gain ( vs. ). In addition, BAT and liver of high-fat-fed mice did not respond to treatment with GC-24 (). The impairment in TRβ
-mediated thyroid hormone signaling was quite remarkable perhaps because treatment with GC-24 started after the animals had been on a HFD for 3 weeks (). A less pronounced impairment in GC-24 signaling by high-fat feeding was also observed in a rat model in which the administration of GC-24 was split into two daily injections versus one single injection in the present study (18
). A mechanistic explanation for such impairment in thyroid hormone (GC-24) signaling is unknown, but as discussed by Pihlajamäki et al.
), it possibly involves a reduction in the Pgc-1
levels, a well-known TR coactivator.
These observations have important clinical implications given that the development of TRβ-selective agonists is aimed at treating the metabolic consequences of obesity and dyslipidemia. If confirmed in a clinical setting, the present findings would indicate that relatively higher doses of TRβ-selective agonists should be used in individuals on a HFD, obese or with liver steatosis. It is possible that feeding a HFD somehow accelerates thyroid hormone/GC-24 catabolism, which would explain the decreased efficiency of these molecules under such settings. However, this hypothesis is unlikely as seen by the modifications in gene expression in the heart of the present animals (), indicating that GC-24 and T3 maintain their biological effects in certain tissues despite the high-fat feeding.
The second point raised by the present findings has to do with the site of action of GC-24, which remains poorly characterized. Our present data confirm that brown adipocytes are a target of GC-24 () and that energy expenditure is accelerated in nonobese animals (). However, the lack of acceleration in energy expenditure in obese animals () and the fact that BAT gene expression was not affected by treatment with GC-24 () indicate otherwise. Of course, it is possible that BAT activation is so limited that cannot be detected by the present analysis, or it does not involve aerobic pathways, or it takes place through a different metabolic pathway not involving the eight key genes studied. The first possibility is more likely given that in obese rats treated with GC-24, some gene induction was observed in BAT (18
). Similar arguments could be used to analyze the involvement of other metabolically relevant tissues, including skeletal muscle, liver, and adipose tissue. While we presently found no evidence that skeletal muscle is a target of GC-24, there are other studies indicating that TRβ
-selective agonists spare the skeletal muscle tissue (28
). At the same time, white adipose tissue is unlikely to be a target of GC-24 in a setting that is similar to the present studies (18
A novel observation brought to light with our data is that treatment with GC-24 does not increase food intake, a well-known effect of T3 (28
). In fact, administration of GC-24 failed to increase further the caloric intake of mice placed on a HFD (). It is well accepted that T3 increases caloric intake as a result of direct actions in the medial-basal hypothalamus (28
) and also indirectly, as a result of the increased energy expenditure (29
). At face value, the present observation indicates that this T3 pathway is mediated via a TRα
mechanism. Given that the brain is a predominantly TRα
-expressing tissue (30
), it is indeed likely that these central (metabolic) effects of T3 are mediated by a TRα
-dependent mechanism. At the same time, it is unknown whether the blood–brain barrier could be playing a role in this pathway selectivity as well. In the periphery, given that tissues such as BAT, skeletal muscle, and liver were not activated in the GC-24-treated animals, it would seem unlikely that indirect effects triggered by GC-24 could increase caloric intake.