Krishna Chatterjee

Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance

Thyroid hormones have widespread cellular effects; however it is unclear whether their effects on the central nervous system (CNS) contribute to global energy balance. Here we demonstrate that either whole-body hyperthyroidism or central administration of triiodothyronine (T3) decreases the activity of hypothalamic AMP-activated protein kinase (AMPK), increases sympathetic nervous system (SNS) activity and upregulates thermogenic markers in brown adipose tissue (BAT). Inhibition of the lipogenic pathway in the ventromedial nucleus of the hypothalamus (VMH) prevents CNS-mediated activation of BAT by thyroid hormone and reverses the weight loss associated with hyperthyroidism. Similarly, inhibition of thyroid hormone receptors in the VMH reverses the weight loss associated with hyperthyroidism. This regulatory mechanism depends on AMPK inactivation, as genetic inhibition of this enzyme in the VMH of euthyroid rats induces feeding-independent weight loss and increases expression of thermogenic markers in BAT. These effects are reversed by pharmacological blockade of the SNS. Thus, thyroid hormone–induced modulation of AMPK activity and lipid metabolism in the hypothalamus is a major regulator of whole-body energy homeostasis.

Resistance to thyroid hormone caused by a mutation in thyroid hormone receptor (TR)α1 and TRα2: clinical, biochemical, and genetic analyses of three related patients

BACKGROUND The thyroid hormone receptor α gene (THRA) transcript is alternatively spliced to generate either thyroid hormone receptor (TR)α1 or a non-hormone-binding variant protein, TRα2, the function of which is unknown. Here, we describe the first patients identified with a mutation in THRA that affects both TRα1 and TRα2, and compare them with patients who have resistance to thyroid hormone owing to a mutation affecting only TRα1, to delineate the relative roles of TRα1 and TRα2. METHODS We did clinical, biochemical, and genetic analyses of an index case and her two sons. We assessed physical and radiological features, thyroid function, physiological and biochemical markers of thyroid hormone action, and THRA sequence. FINDINGS The patients presented in childhood with growth failure, developmental delay, and constipation, which improved after treatment with thyroxine, despite normal concentrations of circulating thyroid hormones. They had similar clinical (macrocephaly, broad faces, skin tags, motor dyspraxia, slow speech), biochemical (subnormal ratio of free thyroxine:free tri-iodothyronine [T3], low concentration of total reverse T3, high concentration of creatine kinase, mild anaemia), and radiological (thickened calvarium) features to patients with TRα1-mediated resistance to thyroid hormone, although our patients had a heterozygous mis-sense mutation (Ala263Val) in both TRα1 and TRα2 proteins. The Ala263Val mutant TRα1 inhibited the transcriptional function of normal receptor in a dominant-negative fashion. By contrast, function of Ala263Val mutant TRα2 matched its normal counterpart. In vitro, high concentrations of T3 restored transcriptional activity of Ala263Val mutant TRα1, and reversed the dominant-negative inhibition of its normal counterpart. High concentrations of T3 restored expression of thyroid hormone-responsive target genes in patient-derived blood cells. INTERPRETATION TRα1 seems to be the principal functional product of the THRA gene. Thyroxine treatment alleviates hormone resistance in patients with mutations affecting this gene, possibly ameliorating the phenotype. These findings will help the diagnosis and treatment of other patients with resistance to thyroid hormone resulting from mutations in THRA. FUNDING Wellcome Trust, NIHR Cambridge Biomedical Research Centre, Marie Curie Actions, Foundation for Development of Internal Medicine in Europe.

Contrasting phenotypes in Resistance to Thyroid Hormone [alpha] correlate with divergent properties of thyroid hormone receptor [alpha]1 mutant proteins

Our research is supported by the Wellcome Trust (Investigator Award 095564/Z/11/Z to KC; Investigator Award 100237/Z/12/Z to JS) and NIHR Cambridge Biomedical Research Centre (CM, KC). JS is a Royal Society Wolfson Research Merit Award Holder.

Magnetic resonance spectroscopy analysis of intramyocellular lipid composition in lipodystrophic patients and athletes

Context Paradoxically, intramyocellular lipid (IMCL) accumulation has been linked to both insulin-resistant and to insulin-sensitive (athletes) states. The composition of this lipid store is unknown in these states. Design and Methods We used a recently validated and potentially widely applicable 1H magnetic resonance spectroscopy method to compare the compositional saturation index (CH2:CH3 ratio) and concentration independent of composition (CH3) of intramyocellular lipid in the soleus and tibialis anterior muscles of 16 female insulin-resistant lipodystrophic patients with that of age- and gender-matched athletes (n=14) and healthy controls (n = 41). Main Outcome IMCL compositional saturation index (CH2:CH3 ratio). Results The IMCL CH2:CH3 ratio was significantly higher in both muscles of the lipodystrophic patients compared with age- and gender-matched controls but not compared to athletes. IMCL CH2:CH3 was dependent on IMCL concentration in the controls and after adjusting the composition index for quantity (CH2:CH3adj) was able to distinguish patients from athletes. With groups pooled, this CH2:CH3adj marker had the strongest relation to insulin resistance (HOMA-IR) compared to other measures of lipid concentration and composition, especially in the soleus muscle. Contrary to the ‘athlete’s paradox’, IMCL in athletes was similar in tibialis anterior (p>0.05) and significantly lower in the soleus (p < 0.004) compared to both controls and patients. Conclusions The IMCL saturation index adjusted for quantity, which likely reflects accumulation of saturated IMCL, is more closely associated with insulin resistance than concentration alone.