Human resident liver myeloid cells protect against metabolic stress in obesity.

Although multiple populations of macrophages have been described in the human liver, their function and turnover in patients with obesity at high risk of developing non-alcoholic fatty liver disease (NAFLD) and cirrhosis are currently unknown. Herein, we identify a specific human population of resident liver myeloid cells that protects against the metabolic impairment associated with obesity. By studying the turnover of liver myeloid cells in individuals undergoing liver transplantation, we find that liver myeloid cell turnover differs between humans and mice. Using single-cell techniques and flow cytometry, we determine that the proportion of the protective resident liver myeloid cells, denoted liver myeloid cells 2 (LM2), decreases during obesity. Functional validation approaches using human 2D and 3D cultures reveal that the presence of LM2 ameliorates the oxidative stress associated with obese conditions. Our study indicates that resident myeloid cells could be a therapeutic target to decrease the oxidative stress associated with NAFLD.

Central Hypothyroidism Impairs Heart Rate Stability and Prevents Thyroid Hormone-Induced Cardiac Hypertrophy and Pyrexia.

Background: Tachycardia, cardiac hypertrophy, and elevated body temperature are major signs of systemic hyperthyroidism, which are considered to reflect the excessive thyroid hormone (TH) action in the respective peripheral tissues. However, recent observations indicate that the central actions of TH also contribute substantially to cardiovascular regulation and thermogenesis. Methods: In this study, we dissect the individual contributions of peripheral TH action versus the central effects in body temperature regulation and cardiovascular functions by taking advantage of mice lacking the TH transporters monocarboxylate transporter 8 (MCT8) and organic anion transporting polypeptide 1C1 (OATP1C1) (M/O double knock-out [dko]), which exhibit elevated serum triiodothyronine (T3) levels while their brain is in a profoundly hypothyroid state. We compared these animals with wild-type (WT) mice that were treated orally with T3 to achieve similarly elevated serum T3 levels, but are centrally hyperthyroid. For the studies, we used radiotelemetry, infrared thermography, gene expression profiling, Western blot analyses, and enzyme linked immunosorbent assays (ELISA) assays. Results: Our analyses revealed mild hyperthermia and cardiac hypertrophy in T3-treated WT mice but not in M/O dko animals, suggesting that central actions of TH are required for these hyperthyroid phenotypes. Although the average heart rate was unaffected in either model, the M/O dko exhibited an altered heart rate frequency distribution with tachycardic bursts in active periods and bradycardic episodes during resting time, demonstrating that the stabilization of heart rate by the autonomic nervous system can be impaired in centrally hypothyroid animals. Conclusions: Our studies unravel distinct phenotypical traits of hyperthyroidism that depend on an intact central nervous system, and provide valuable insight into the cardiovascular pathology of the Allan-Herndon-Dudley syndrome, a condition caused by the lack of MCT8 in humans.

CD5L Constitutes a Novel Biomarker for Integrated Hepatic Thyroid Hormone Action.

Background: Pathological conditions of the thyroid hormone (TH) system are routinely diagnosed by using serum concentrations of thyrotropin (TSH), which is sufficient in most cases. However, in certain conditions, such as resistance to TH due to mutations in THRB (RTHb) or TSH-releasing pituitary adenoma (TSHoma), TSH may be insufficient for a correct diagnosis, even in combination with serum TH concentrations. Likewise, under TH replacement therapy, these parameters can be misleading and do not always allow optimal treatment. Hence, additional biomarkers to assess challenging clinical conditions would be highly beneficial. Methods: Data from untargeted multi-omics analyses of plasma samples from experimental thyrotoxicosis in human and mouse were exploited to identify proteins that might represent possible biomarkers of TH function. Subsequent mouse studies were used to identify the tissue of origin and the involvement of the two different TH receptors (TR). For in-depth characterization of the underlying cellular mechanisms, primary mouse cells were used. Results: The analysis of the plasma proteome data sets revealed 16 plasma proteins that were concordantly differentially abundant under thyroxine treatment compared with euthyroid controls across the two species. These originated predominantly from liver, spleen, and bone. Independent studies in a clinical cohort and different mouse models identified CD5L as the most robust putative biomarker under different serum TH states and treatment periods. In vitro studies revealed that CD5L originates from proinflammatory M1 macrophages, which are similar to liver-residing Kupffer cells, and is regulated by an indirect mechanism requiring the secretion of a yet unknown factor from hepatocytes. In agreement with the role of TRα1 in immune cells and the TRß-dependent hepatocyte-derived signaling, the in vivo regulation of Cd5l expression depended on both TR isoforms. Conclusion: Our results identify several novel targets of TH action in serum, with CD5L as the most robust marker. Although further studies will be needed to validate the specificity of these targets, CD5L seems to be a promising candidate to assess TH action in hepatocyte-macrophage crosstalk.

Unraveling the Molecular Basis for Successful Thyroid Hormone Replacement Therapy: The Need for New Thyroid Tissue- and Pathway-Specific Biomarkers.

Thyroid function is conventionally assessed by measurement of thyroid-stimulating hormone (TSH) and free circulating thyroid hormones, which is in most cases sufficient for correct diagnosis and monitoring of treatment efficiency. However, several conditions exist, in which these parameters may be insufficient or even misleading. For instance, both, a TSH-secreting pituitary adenoma and a mutation of thyroid hormone receptor ß present with high levels of TSH and circulating hormones, but the optimal treatment is substantially different. Likewise, changes in thyroid hormone receptor α signaling are not captured by routine assessment of thyroid status, as serum parameters are usually inconspicuous. Therefore, new biomarkers are urgently needed to improve the diagnostic management and monitor treatment efficiency for e. g., replacement therapy in hypothyroidism or thyroid hormone resistance. By comparing animal models to human data, the present minireview summarizes the status of this search for new tissue- and pathway-specific biomarkers of thyroid hormone action.

Thyroid-Hormone-Induced Browning of White Adipose Tissue Does Not Contribute to Thermogenesis and Glucose Consumption.

Regulation of body temperature critically depends on thyroid hormone (TH). Recent studies revealed that TH induces browning of white adipose tissue, possibly contributing to the observed hyperthermia in hyperthyroid patients and potentially providing metabolic benefits. Here, we show that browning by TH requires TH-receptor ß and occurs independently of the sympathetic nervous system. The beige fat, however, lacks sufficient adrenergic stimulation and is not metabolically activated despite high levels of uncoupling protein 1 (UCP1). Studies at different environmental temperatures reveal that TH instead causes hyperthermia by actions in skeletal muscle combined with a central body temperature set-point elevation. Consequently, the metabolic and thermogenic effects of systemic hyperthyroidism were maintained in UCP1 knockout mice, demonstrating that neither beige nor brown fat contributes to the TH-induced hyperthermia and elevated glucose consumption, and underlining that the mere presence of UCP1 is insufficient to draw conclusions on the therapeutic potential of browning agents.

Aortic effects of thyroid hormone in male mice.

It is well established that thyroid hormones are required for cardiovascular functions; however, the molecular mechanisms remain incompletely understood, especially the individual contributions of genomic and non-genomic signalling pathways. In this study, we dissected how thyroid hormones modulate aortic contractility. To test the immediate effects of thyroid hormones on vasocontractility, we used a wire myograph to record the contractile response of dissected mouse aortas to the adrenergic agonist phenylephrine in the presence of different doses of T3 (3,3',5-triiodothyronine). Interestingly, we observed reduced vasoconstriction under low and high T3 concentrations, indicating an inversed U-shaped curve with maximal constrictive capacity at euthyroid conditions. We then tested for possible genomic actions of thyroid hormones on vasocontractility by treating mice for 4 days with 1 mg/L thyroxine in drinking water. The study revealed that in contrast to the non-genomic actions the aortas of these animals were hyperresponsive to the contractile stimulus, an effect not observed in endogenously hyperthyroid TRß knockout mice. To identify targets of genomic thyroid hormone action, we analysed aortic gene expression by microarray, revealing several altered genes including the well-known thyroid hormone target gene hairless. Taken together, the findings demonstrate that thyroid hormones regulate aortic tone through genomic and non-genomic actions, although genomic actions seem to prevail in vivo. Moreover, we identified several novel thyroid hormone target genes that could provide a better understanding of the molecular changes occurring in the hyperthyroid aorta.