Obesity is a major global health concern, increasing the risk of metabolic diseases and premature death. Innovative strategies are required to combat obesity, including better understanding the molecular mechanisms underlying brown adipose tissue (BAT) development and physiology, as BAT serves as a natural defense against cold and obesity. This article delves into the intricate relationship between thyroid hormones, specifically T3, weight loss, and the function of thyroid-stimulating hormone (TSH) levels, examining the impact of glucagon-like peptide-1 (GLP-1) medications and other related factors.
Thyroid Hormones and Weight Loss: An Established Connection
The association between thyroid hormones and weight loss has been documented in previous research. A 2014 study published in Thyroid determined that moderate dietary restriction in participants with a body mass index of 25 to 45 kg/m2 resulted in a 6.3 ± 0.9 kg (6.5 ± 1.0%) weight loss. At baseline, TSH levels and T3 concentrations were significantly associated with fat mass. After weight loss, T3 decreased significantly (from 112.7 ± 3.1 to 101.8 ± 2.6 ng/dL, P < .001) in the absence of significant changes in TSH or free T4. Additionally, the T3 to free T4 ratio decreased significantly in those who lost more than 5% of their body weight.
GLP-1 Medications, Weight Change, and TSH Levels: Exploring the Interplay
Knowing the associations between the thyroid and weight loss, investigators have aimed to further understand the relationships between GLP-1 medications, weight change, and TSH levels. GLP-1 medications, such as semaglutide (Ozempic, Weygovy; Novo Nordisk), dulaglutide (Trulicity; Eli Lilly and Co), liraglutide (Victoza; Novo Nordisk), or exenatide (Byetta; Eli Lilly and Co), are often prescribed for managing diabetes and obesity.
Impact of Weight Loss on TSH Levels in Hypothyroid Patients
A study conducted by Epic Research found that patients with a history of hypothyroidism who were prescribed a GLP-1 medication and lost more than 5 pounds experienced a reduction in their TSH levels. According to the study findings, patients who were prescribed semaglutide and lost over 5 pounds saw the greatest reduction of their TSH levels (-0.55 mU/L). Within this subgroup, exenatide demonstrated the smallest reduction in TSH (-0.36 mU/L). Semaglutide had different effects in the “lost 0 to 5 pound” group and weight gain group, demonstrating TSH changes of -0.27 mU/L and 0.04, respectively. Additionally, exenatide was the only GLP-1 medication that resulted in a decrease in TSH levels (-0.05 mU/L) in the weight gain group, but the investigators noted that this group saw no statistically significant changes in their levels. In contrast, those who gained weight had no statistically significant change in their TSH levels. These findings are significant in understanding interactions between glucagon-like peptide-1 medications and thyroid dysfunction because prior research has shown conflicting results.
Conflicting Evidence and the Need for Further Research
Because thyroid dysfunction can often occur with metabolic conditions, such as diabetes and obesity, investigators of a June 2024 review published in Biomolecules aimed to find a deeper understanding of GLP-1 medications’ interactions with thyroid dysfunction and intended to clarify the safety of GLP-1 medications in patients who have both diabetes and thyroid disorders. These authors determined that although multiple studies have explored these associations, the current evidence is inconclusive because of conflicting results. However, an interaction between thyroid dysfunction and metabolic conditions was confirmed. They suggested that because-as of the study’s publication-there are no guidelines to provide definitive directions, thyroid function tests in routine screening of patients with diabetes should be performed, particularly on those who are being treated with GLP-1 medications. With these data, additional research will be needed to confirm findings. The authors of the review in Biomolecules suggest that larger sample sizes and longer-term studies may help gather clearer results.
Read also: Achieve Weight Loss with CrossFit
The Role of T3 in Brown Adipose Tissue and Thermogenesis
As a thermogenic hormone, thyroid hormone (TH) is necessary for a full metabolic response of BAT under maximal demands. Apart from its role in regulating thermogenic capacity of mature brown adipocytes either directly or via sympathetic nervous system, TH can enhance the hyperplastic growth of interscapular BAT (iBAT), a classic brown fat depot.
T3's Impact on iBAT Expansion and Thermogenic Capacity
To understand the profound effect of TH on the recruitment process of iBAT, mice were rendered hypothyroid by using MMI (MMI mice) followed by intraperitoneal (i.p.) T3 treatment for 4 h (short-term) or 5 days (long-term). Long-term treatment of T3 increased not only the dorsal skin temperature (Tskin) in the interscapular area, but also the core body temperature (Tcore) as assessed via rectal thermometry (Trectal) of MMI mice, indicating that long-term T3 treatment is able to enhance the thermogenic capacity of iBAT. Analysis of UCP1 recruitment in iBAT depot revealed that short-term T3 treatment increased the levels of either UCP1 protein per mg tissue protein or UCP1 protein per depot in these mice, which might be attributed to the upregulation of Ucp1 mRNA levels by T3.
Interestingly, although decreased rather than increased Ucp1 mRNA levels were observed after long-term T3 treatment, UCP1 protein levels per mg tissue protein were similarly increased after long-term T3 treatment. Notably, although the UCP1 protein levels per mg tissue protein were not further increased by long-term T3 treatment compared to short-term treatment, the total amount of UCP1 protein per depot was further increased by long-term T3 treatment. As T3 treatment had no effect on the stability of UCP1 protein, the above results imply that there were more UCP1-expressing cells after long-term T3 treatment. These results also suggest that the sustained elevation of the total amount of UCP1 protein per depot might be responsible for the increase in thermogenic capacity of iBAT observed by surface infrared thermography after long-term T3 treatment.
In accordance with the greatly increased thermogenic capacity, the iBAT depot was enlarged after long-term T3 treatment in MMI mice, as evident from increased size and weight of iBAT. Importantly, long-term treatment of T3 increased the number of both stromal vascular fraction (SVF) cells and mature adipocytes from the iBAT depot, indicating that iBAT expands extensively through hyperplastic growth during T3-induced recruitment of thermogenic capacity. In contrast, the number of either SVF cells or mature adipocytes was not significantly increased after short-term T3 treatment. Consistently, the decreases in iBAT size, weight, and number of SVF cells were observed in the iBAT of hypothyroid MMI mice compared to euthyroid control mice, which was accompanied with decreases in either interscapular Tskin or Tcore. Above results suggest that T3 might be of physiological importance in modulating the thermogenic capacity through promoting the hyperplastic growth of iBAT.
T3's Influence on Adipocyte Progenitor Cells (APCs)
Given that APCs residing in fat depot are able to undergo mitotic proliferation and adipogenic differentiation, thereby generating a functional adipose depot in vivo, we speculated that the enlargement of iBAT depot by long-term T3 treatment involves the proliferation of APCs. To test this hypothesis, we performed flow cytometry and fluorescence-activated cell sorting (FACS) analysis by using the SVF derived from the iBAT depot. We found that T3 treatment in MMI mice could increase both the number of APCs (CD45−CD31−Sca1+ cells) and the percentage of APCs in either total live cells or CD45− nonhematopoietic (Lin−) SVF cells in a dose- and time-dependent manner. Notably, the number and percentage of CD45+ cells in the stromal compartment were increased or tended to be increased dose- and time-dependently by T3 treatment, suggesting that immune cells are also likely involved in the T3-induced iBAT expansion. Consistent with above results, decreases in the number and percentage of APCs were observed in the iBAT of hypothyroid mice compared to euthyroid mice, suggesting that T3 might be of physiological importance in maintaining the APC pool in iBAT depot.
Read also: Transformations with Ozempic
Furthermore, 5-bromo-2-deoxyuridine (BrdU) or 5-ethynyl-2-deoxyuridine (EdU) label retention was employed to identify newly generated cells in the iBAT of MMI mice after T3 treatment. Fluorescence microscopy analysis revealed that EdU+ cells could be observed after T3 treatment but barely detectable in the iBAT of MMI mice without T3 treatment. Analysis of in vivo BrdU labeling by flow cytometry revealed a gradual increase in both the number and the percentage of BrdU+ APCs after daily T3 injections in MMI mice. Notably, the number of BrdU+ APCs reached the highest point when the percentage of BrdU+ APCs reached a peak at day 4 after T3 injections in MMI mice. Accordingly, staining intensity of proliferation marker Ki67 in APCs was increased gradually and reached the highest point after 4 days of T3 treatment. These results indicate that T3 induces the proliferation of APCs to expand the progenitor population in iBAT depot. Consistently, increases in the percentage of BrdU+ cells and the Ki67 staining intensity were observed in a T3-treated brown adipocyte precursor cell line (BAC). These data and those from the experiments performed at 30°C, using adrenergic receptor antagonists, with intracerebroventricular injection of T3, and using microneedles for local delivery of T3 to iBAT region suggest that T3 can target APCs resided in iBAT directly and promoting APC proliferation in a cell-autonomous manner.
The Role of TRα in T3-Mediated iBAT Hyperplasia
TRα and TRβ mediate most actions of T3, which are expressed in a tissue-specific and developmentally-regulated manner. To determine which TR isoform is responsible for the T3 effect on the hyperplastic growth of iBAT, especially the APC proliferation, the expression of TRα and TRβ in the cultured SVF cells, APCs derived from iBAT, as well as SVF-derived mature brown adipocytes was examined. We found that the mRNA levels of TRα are 10 times higher than those of TRβ in either freshly isolated APCs or cultured APC-enriched SVF cells, suggesting that TRα might be the major TR isoform mediating the T3 effect on APCs in iBAT.
T3 and Weight Management: Considerations and Cautions
While T3 plays a crucial role in metabolism and can influence weight, it is essential to approach its use for weight management with caution. Cytomel, a synthetic form of T3, is sometimes prescribed for hypothyroidism, and while it can aid in weight loss for individuals with low thyroid levels, it is not a safe or effective weight loss solution for those with normal thyroid function.
Risks of Cytomel Overdose and Toxicity
Using high dosages of Cytomel to reduce weight in people with normal thyroid levels is dangerous and can be life-threatening. Strokes, seizures, shock, coma, and death have been reported in people who have taken higher than recommended dosages of Cytomel. Some symptoms of Cytomel toxicity (overdose), such as confusion, disorientation, or heart changes, may not appear until several days after ingestion.
Cytomel has a narrow therapeutic index, meaning there is a fine line between taking too much or having too little. Over or under treatment can be detrimental to a young person’s growth and development, cardiovascular function, bone metabolism, reproductive health, emotional state, gastrointestinal function, and glucose and lipid metabolism.
Read also: Weight Loss with Cryotherapy: What to Expect
Combination Therapy with Cytomel and Synthroid
Although the American Thyroid Association guidelines do not recommend taking Cytomel and Synthroid together, many people who are under the supervision of an internist/endocrinologist do take this combination treatment, prefer it, and have good results on it. Never take this combination without your doctor's advice because it may result in excessive levels of thyroid hormones which can be dangerous.
T3 vs. T4 Therapy: A Comparative Analysis
Levothyroxine (l-T4) therapy is based on the assumption that the conversion of T4 into T3 provides adequate amounts of active hormone at target tissues. However, in rodents, l-T4 alone does not restore a euthyroid state in all tissues.
In a study comparing l-T3 and l-T4 treatments, no difference was observed in TSH between the two therapies. However, l-T3 resulted in significant weight loss and in a decrease in total cholesterol, low-density lipoprotein-cholesterol, and apolipoprotein B.
The substitution of l-T3 for l-T4 caused a significant weight loss. TH is the major regulator of basal metabolic rate (32), so it is likely that this weight reduction is due to an increase in metabolic rate rather than a decrease in food intake. The lack of a detectable change in REE is likely due to the small magnitude of the effect, because a negative energy balance …