Metabolic profiling reveals reprogramming of lipid metabolic pathways in treatment of polycystic ovary syndrome with 3-iodothyronamine

Complex diseases such as polycystic ovary syndrome (PCOS) are associated with intricate pathophysiological, hormonal, and metabolic feedbacks that make their early diagnosis challenging, thus increasing the prevalence risks for obesity, cardiovascular, and fatty liver diseases. To explore the crosstalk between endocrine and lipid metabolic pathways, we administered 3-iodothyronamine (T1AM), a natural analog of thyroid hormone, in a mouse model of PCOS and analyzed plasma and tissue extracts using multidisciplinary omics and biochemical approaches. T1AM administration induces a profound tissue-specific antilipogenic effect in liver and muscle by lowering gene expression of key regulators of lipid metabolism, PTP1B and PLIN2, significantly increasing metabolites (glucogenic, amino acids, carnitine, and citrate) levels, while enhancing protection against oxidative stress. In contrast, T1AM has an opposing effect on the regulation of estrogenic pathways in the ovary by upregulating STAR, CYP11A1, and CYP17A1. Biochemical measurements provide further evidence of significant reduction in liver cholesterol and triglycerides in post-T1AM treatment. Our results shed light onto tissue-specific metabolic vs. hormonal pathway interactions, thus illuminating the intricacies within the pathophysiology of PCOS. This study opens up new avenues to design drugs for targeted therapeutics to improve quality of life in complex metabolic diseases

Metabolic reprogramming by 3-Iodothyronamine (T1AM): a new perspective to reverse obesity through co-regulation of sirtuin 4 and 6 expression

Obesity is a complex disease associated with environmental and genetic factors. 3-Iodothyronamine (T1AM) has revealed great potential as an effective weight loss drug. We used metabolomics and associated transcriptional gene and protein expression analysis to investigate the tissue specific metabolic reprogramming effects of subchronic T1AM treatment at two pharmacological daily doses (10 and 25 mg/kg) on targeted metabolic pathways. Multi-analytical results indicated that T1AM at 25 mg/kg can act as a novel master regulator of both glucose and lipid metabolism in mice through sirtuin-mediated pathways. In liver, we observed an increased gene and protein expression of Sirt6 (a master gene regulator of glucose) and Gck (glucose kinase) and a decreased expression of Sirt4 (a negative regulator of fatty acids oxidation (FAO)), whereas in white adipose tissue only Sirt6 was increased. Metabolomics analysis supported physiological changes at both doses with most increases in FAO, glycolysis indicators and the mitochondrial substrate, at the highest dose of T1AM. Together our results suggest that T1AM acts through sirtuin-mediated pathways to metabolically reprogram fatty acid and glucose metabolism possibly through small molecules signaling. Our novel mechanistic findings indicate that T1AM has a great potential as a drug for the treatment of obesity and possibly diabetes

Lipolytic effects of endogenous 3-iodothyronamine (T1AM) and synthetic analog SG-2 in vivo and in cultured adipocytes

3-Iodothyronamine (T1AM) is a hormone like molecule structurally similar to TH, that has been reported to modulate energy metabolism by favoring lipid over glucose catabolism. To better understand the role played by T1AM on the regulation of lipid metabolism, in the present study we administered spontaneously obese mice with T1AM at two different dosages (10 and 25 mg/kg per day) for 7 days and the effects on body weight (BW) and lipid profiles were examined. In addition a fluoro-labeled version of T1AM (FL-T1AM) was synthesized and utilized to assess T1AM intracellular localization in 3T3-L1 mouse adipocytes. Administration of 10 or 25 mg/kg per day T1AM showed a BW loss of 10% or 18% of initial BW by day 7 of treatment. T1AM treatment at both dosages produced a significant increase in total plasma triglycerides (P<0.05) and a significant decrease in plasma cholesterol (P<0.05), without any significant change in glycaemia. At present, the specific mechanism of T1AM entry into the cell, as well as its internal targets remains unknown. Cellular imaging revealed rapid intercellular uptake of FL-T1AM without localization to the lipid droplet or nucleus of mature adipocytes. This rapid rate of uptake was further evaluated via flow cytometry, with peak detection of FL-T1AM steadily rising until reaching peak signal and equilibrium at ~20 min. We also observed that when 3T3-L1 adipocytes were treated with T1AM or its synthetic halogen free analog SG-2 (1–10 μM), both compounds decreased lipid accumulation in mature adipocytes, with SG-2 showing a potency significantly higher than T1AM (IC50SG-2=5 μM; IC50T1AM=20 μM). In conclusion T1AM and its synthetic analog show a significant lipolytic activity, both in cultured adipocytes and in vivo

Loss of Hepatic Mitochondrial Long-Chain Fatty Acid Oxidation Confers Resistance to Diet-Induced Obesity and Glucose Intolerance

The liver has a large capacity for mitochondrial fatty acid β-oxidation, which is critical for systemic metabolic adaptations such as gluconeogenesis and ketogenesis. To understand the role of hepatic fatty acid oxidation in response to a chronic high-fat diet (HFD), we generated mice with a liver-specific deficiency of mitochondrial long-chain fatty acid β-oxidation (Cpt2L-/- mice). Paradoxically, Cpt2L-/- mice were resistant to HFD-induced obesity and glucose intolerance with an absence of liver damage, although they exhibited serum dyslipidemia, hepatic oxidative stress, and systemic carnitine deficiency. Feeding an HFD induced hepatokines in mice, with a loss of hepatic fatty acid oxidation that enhanced systemic energy expenditure and suppressed adiposity. Additionally, the suppression in hepatic gluconeogenesis was sufficient to improve HFD-induced glucose intolerance. These data show that inhibiting hepatic fatty acid oxidation results in a systemic hormetic response that protects mice from HFD-induced obesity and glucose intolerance.publishe

The mitochondrial carrier SFXN1 is critical for complex III integrity and cellular metabolism.

Mitochondrial carriers (MCs) mediate the passage of small molecules across the inner mitochondrial membrane (IMM), enabling regulated crosstalk between compartmentalized reactions. Despite MCs representing the largest family of solute carriers in mammals, most have not been subjected to a comprehensive investigation, limiting our understanding of their metabolic contributions. Here, we functionally characterize SFXN1, a member of the non-canonical, sideroflexin family. We find that SFXN1, an integral IMM protein with an uneven number of transmembrane domains, is a TIM22 complex substrate. SFXN1 deficiency leads to mitochondrial respiratory chain impairments, most detrimental to complex III (CIII) biogenesis, activity, and assembly, compromising coenzyme Q levels. The CIII dysfunction is independent of one-carbon metabolism, the known primary role for SFXN1 as a mitochondrial serine transporter. Instead, SFXN1 supports CIII function by participating in heme and α-ketoglutarate metabolism. Our findings highlight the multiple ways that SFXN1-based amino acid transport impacts mitochondrial and cellular metabolic efficiency