Reduced expression of uncoupling protein 2 in adipose tissue in patients with hypothyroidism.

CONTEXT: Thyroid disease is associated with major metabolic changes, comprising changes in lipid metabolism. Thyroid hormones have previously been shown to increase UCP2 mRNA expression in fat biopsies from hyperthyroid patients, but data from hypothyroid patients have so far not been reported. PATIENTS AND METHODS: Eleven hypothyroid patients were studied before and after l-T(4) replacement, and 10 healthy controls matched for sex, age, and body mass index were studied once. Subcutaneous fat biopsies were performed, and UCP2 mRNA expression was measured in these biopsies. Patients also underwent indirect calorimetry and blood sampling. RESULTS: Patients were profoundly hypothyroid at study entry with significantly increased TSH levels (149.9 + or - 60.4 mU/liter). UCP2 mRNA expression was reduced in the hypothyroid state as compared with the euthyroid state (0.0081 + or - 0.0028 vs. 0.0420 + or - 0.0076, P < 0.01). Using pooled data from hypothyroid patients and control subjects, we found positive correlations between lipid oxidation rates and adipose tissue UCP2 expression (r = 0.63; P < 0.004), basal free fatty acid levels and UCP2 expression (r = 0.51; P < 0.03), and T(3) levels and UCP2 (r = 0.69; P < 0.001). CONCLUSION: Our study demonstrates that hypothyroidism is associated with a profound decrease in UCP2 mRNA expression. It supports the notion that UCP2 is a determinant of fat oxidation pathways and may be involved in the changes seen in the metabolic pathways in thyroid disease.

Increased protein turnover and proteolysis is an early and primary feature of short-term experimental hyperthyroidism in healthy women.

CONTEXT: Hyperthyroidism increases energy expenditure, glucose turnover, lipolysis, and protein breakdown. OBJECTIVE: Our objective was to test whether increased protein breakdown occurs independently of other catabolic effects in mild experimental hyperthyroidism. DESIGN: We conducted a single-blind, randomized, placebo-controlled, crossover study. Protein dynamics of the whole body and of the forearm muscles were measured by amino acid tracer dilution technique ([(15)N]phenylalanine and [(2)H(4)]tyrosine). All subjects underwent a 3-h study in the basal state followed by a 3-h euglycemic clamp study. SETTING: The study took place at a university clinical research unit. PARTICIPANTS: Eight healthy women (24-46 yr old) participated. INTERVENTION: Intervention included 6 d thyroid hormone (T(4) 50 microg and T(3) 0.67 microg/kg.d) or placebo administration. RESULTS: Thyroid hormone administration led to mild T(3) hyperthyroidism with more than a doubling of T(3) levels and suppression of TSH. Energy expenditure and body composition was unchanged. Glucose infusion rates, forearm glucose uptake, and levels of lipid intermediates were also alike. Basal whole-body phenylalanine flux and tyrosine flux (reflecting whole-body protein breakdown) were increased (P < 0.05) as were whole-body protein synthesis rate (P = 0.05). Basal forearm rate of appearance and disappearance for phenylalanine (reflecting muscle protein breakdown and synthesis) were similar. CONCLUSIONS: Mild short-term experimental hyperthyroidism increases whole-body protein turnover and breakdown before any measurable changes in energy expenditure or glucose and fat metabolism, suggesting that amino acid and protein metabolism is an early and primary target for thyroid hormone action in humans.

Serum ghrelin levels are increased in hypothyroid patients and become normalized by L-thyroxine treatment.

CONTEXT: An interaction between ghrelin, which is implicated in the regulation of short- and long-term energy balance, and thyroid function has been reported in hyperthyroidism in which ghrelin levels are reversibly suppressed. We measured serum ghrelin levels and metabolic indices in hypothyroid patients before and after L-thyroxine replacement. PATIENTS AND METHODS: Eleven patients were examined twice: 1) in the hypothyroid state and 2) after at least 2 months of euthyroidism. Ten healthy subjects served as a control group. Ghrelin was measured in conjunction with indirect calorimetry and a hyperinsulinemic euglycemic clamp. RESULTS: Serum ghrelin levels were increased by 32% under basal conditions in the hypothyroid state (PRE) as compared with posttreatment (POST) (picograms per milliliter): 976.4 +/- 80.8 vs. 736.8 +/- 67.1 (P < 0.001). This difference prevailed during the clamp, but a decline was observed in both states: 641.4 +/- 82.2 vs. 444.3 +/- 66.8 microg/ml (P = 0.005). The hypothyroid state was associated with decreased resting energy expenditure, increased respiratory quotient, and insulin resistance. Serum ghrelin levels as well as the metabolic aberrations became normalized after L-thyroxine replacement as compared with the control subjects. CONCLUSION: Serum ghrelin levels are reversibly increased in hypothyroid patients. It remains to be investigated whether this represents a direct effect of iodothyronines on ghrelin secretion or clearance or a compensatory response to the abnormal energy metabolism in hypothyroid patients.

Thyroid hormone increases mannan-binding lectin levels.

BACKGROUND: Recent studies have indicated the existence of causal links between the endocrine and immune systems and cardiovascular disease. Mannan-binding lectin (MBL), a protein of the innate immune system, may constitute a connection between these fields. METHODS: To test whether thyroid hormone regulates MBL levels, we studied eight patients with Graves' hyperthyroidism before and after methimazole therapy, eight healthy subjects before and after short-term experimental hyperthyroidism, and eight hypothyroid patients with chronic auto-immune thyroiditis before and after L-thyroxine substitution. RESULTS: In all hyperthyroid patients, MBL levels were increased--median (range), 1886 ng/ml (1478-7344) --before treatment and decreased to 954 ng/ml (312-3222) after treatment (P = 0.01, paired comparison: Wilcoxon's signed ranks test). The healthy subjects had MBL levels of 1081 ng/ml (312-1578). Administration of thyroid hormones to these persons induced mild hyperthyroidism and increased MBL levels significantly to 1714 ng/ml (356-2488) (P = 0.01). Two of the eight hypothyroid patients had undetectably low levels of MBL both before and after L-thyroxine substitution. The other six hypothyroid patients had decreased levels of MBL of 145 ng/ml (20-457) compared with 979 ng/ml (214-1533) after L-thyroxine substitution (P = 0.03, paired comparison: Wilcoxon's signed ranks test). CONCLUSION: Our data show that thyroid hormone increases levels of MBL. MBL is part of the inflammatory complement system, and this modulation of complement activation may play a role in the pathogenesis of a number of key components of thyroid diseases.

Whole body and forearm substrate metabolism in hyperthyroidism: evidence of increased basal muscle protein breakdown.

Thyroid hormones have significant metabolic effects, and muscle wasting and weakness are prominent clinical features of chronic hyperthyroidism. To assess the underlying mechanisms, we examined seven hyperthyroid women with Graves' disease before (Ht) and after (Eut) medical treatment and seven control subjects (Ctr). All subjects underwent a 3-h study in the postabsorptive state. After regional catheterization, protein dynamics of the whole body and of the forearm muscles were measured by amino acid tracer dilution technique using [15N]phenylalanine and [2H4]tyrosine. Before treatment, triiodothyronine was elevated (6.6 nmol/l) and whole body protein breakdown was increased 40%. The net forearm release of phenylalanine was increased in hyperthyroidism (microg.100 ml(-1).min(-1)): -7.0 +/- 1.2 Ht vs. -3.8 +/- 0.8 Eut (P = 0.04), -4.2 +/- 0.3 Ctr (P = 0.048). Muscle protein breakdown, assessed by phenylalanine rate of appearance, was increased (microg.100 ml(-1).min(-1)): 15.5 +/- 2.0 Ht vs. 9.6 +/- 1.4 Eut (P = 0.03), 9.9 +/- 0.6 Ctr (P = 0.02). Muscle protein synthesis rate did not differ significantly. Muscle mass and muscle function were decreased 10-20% before treatment. All abnormalities were normalized after therapy. In conclusion, our results show that hyperthyroidism is associated with increased muscle amino acid release resulting from increased muscle protein breakdown. These abnormalities can explain the clinical manifestations of sarcopenia and myopathy.

Hyperthyroidism and cation pumps in human skeletal muscle.

Skeletal muscle constitutes the major target organ for the thermogenic action of thyroid hormone. We examined the possible relation between energy expenditure (EE), thyroid status, and the contents of Ca2+-ATPase and Na+-K+-ATPasein human skeletal muscle. Eleven hyperthyroid patients with Graves' disease were studied before and after medical treatment with methimazole and compared with eight healthy subjects. Muscle biopsies were taken from the vastus lateralis muscle, and EE was determined by indirect calorimetry. Before treatment, the patients had two- to fivefold elevated total plasma T3 and 41% elevated EE compared with when euthyroidism had been achieved. In hyperthyroidism, the content of Ca2+-ATPase was increased: (mean +/- SD) 6,555 +/- 604 vs. 5,212 +/- 1,580 pmol/g in euthyroidism (P = 0.04) and 4,523 +/- 1,311 pmol/g in healthy controls (P = 0.0005). The content of Na+-K+-ATPase showed 89% increase in hyperthyroidism: 558 +/- 101 vs. 296 +/- 34 pmol/g (P = 0.0001) in euthyroidism and 278 +/- 52 pmol/g in healthy controls (P < 0.0001). In euthyroidism, the contents of both cation pumps did not differ from those of healthy controls. The Ca2+-ATPase content was significantly correlated to plasma T3 and resting EE. This provides the first evidence that, in human skeletal muscle, the capacity for Ca2+ recycling and active Na+-K+ transport are correlated to EE and thyroid status.

Hyperthyroidism is associated with suppressed circulating ghrelin levels.

Ghrelin stimulates GH secretion as well as appetite and food intake. To explore whether ghrelin is involved in the regulation of appetite and body weight in hyperthyroidism, circulating ghrelin levels were measured in nine hyperthyroid patients before and after medical treatment and compared with those in eight healthy control subjects. All participants were studied in the postabsorptive state and during a 3-h euglycemic hyperinsulinemic clamp. Before treatment the patients had 3- to 5-fold elevations of T(3), and during treatment the patients gained 5 kg of body weight. Ghrelin levels were decreased in hyperthyroidism both in the fasting state (hyperthyroid, 1080 +/- 195 pg/ml; euthyroid, 1480 +/- 215 pg/ml; P = 0.03) and during clamp (hyperthyroid, 833 +/- 150 pg/ml; euthyroid, 1210 +/- 180 pg/m; P = 0.02). After treatment, ghrelin levels did not differ from those in control subjects. In all three study groups the clamp significantly reduced ghrelin levels compared with fasting levels. In conclusion, ghrelin levels are reduced in hyperthyroidism and become normalized by medical antithyroid treatment. Hyperinsulinemia suppresses ghrelin regardless of thyroid status. Ghrelin is not a primary stimulator of appetite and food intake in hyperthyroidism, and the mechanisms underlying the suppressive effect of hyperthyroidism on ghrelin secretion remain unclear.

Elevated regional lipolysis in hyperthyroidism.

Hyperthyroidism is characterized by increased levels of circulating free fatty acids (FFA) and increased lipid oxidation, but it is uncertain which regional fat depots contribute. The present study was designed to define the participation of femoral and abdominal fat stores in the overall stimulation of lipolysis in hyperthyroidism in the basal state and during insulin stimulation. We studied nine women with newly diagnosed hyperthyroidism (HT) and after (euthyroidism, ET) medical treatment with methimazol and compared with eight control subjects (CTR). All subjects were studied in the postabsorptive state and during a 3-h hyperinsulinemic euglycemic clamp with microdialysis catheters sc in the abdominal and femoral adipose tissue. Before treatment, patients had elevated circulating concentrations of triiodthyronine, FFA, and glycerol. Levels of interstitial glycerol ( micro mol/liter) in abdominal adipose tissue [485 +/- 24 (HT), 226 +/- 20 (ET) (P < 0.001), 265 +/- 34 (CTR) (P < 0.001)] and in femoral adipose tissue [468 +/- 41(HT), 245 +/- 29 (ET) (P < 0.01), 278 +/- 31(CTR) (P < 0.005)] were elevated in the basal hyperthyroid state, and these differences prevailed during the glucose clamp [230 +/- 23 (HT), 113 +/- 13 (ET) (P < 0.01), 132 +/- 22(CTR) (P < 0.01) and 303 +/- 39 (HT), 122 +/- 15 (ET) (P < 0.01), 166 +/- 21(CTR) (P < 0.01)]. These results suggest that femoral and abdominal adipose tissue contribute equally to the excessive rate of lipolysis in hyperthyroidism and that both tissues are resistant to the actions of insulin.