Thyroid Hormone Action in Liver: A Coregulator Shift Rather Than the Canonical Switch

Thyroid hormone receptors (TR) are transcription factors that mediate the effects of thyroid hormones (TH) in development, physiology, and metabolism. TR canonically activates gene expression via a “switch” whereby TH converts chromatin-bound TR from a transcriptional repressor to an activator. In this model, the unliganded repressed state is mediated by binding of the nuclear receptor corepressor (NCoR), while the TH-activated state is caused by dismissal of NCoR and stabilization of binding of coactivators including CREB-binding protein (CBP). TH also negatively regulates gene expression, although the mechanism is controversial. Elucidation of the TR transcriptional mechanism in vivo has been hampered by the low concentration of endogenous TRs and the unavailability of high quality antibodies. To address this, we generated a mouse line in which endogenous TRβ1 was epitope-tagged to allow precise analysis at physiological levels, and explored TR function in liver where the actions of TR regulate body weight, cholesterol, and liver fat. ChIP-seq analysis revealed TRβ binding at genomic sites with epigenomic characteristics of enhancers, at sequences enriched for the canonical DR4 motif bound by TR with its RXR partner, at both positively- as well as negatively-regulated genes. The NCoR/HDAC3 corepressor complex was reduced but not completely dismissed by TH at positive enhancers and, surprisingly, at enhancers associated with negatively. CBP binding was also not “all or none” but, rather, shifted toward increased binding at enhancers in their active state, i.e., in the presence of TH for activated genes, but in the absence of TH for repressed genes. Thus, TH action is due to a shift, not an on/off switch, in coregulator association with TRβ-regulated enhancers determines their activity and transcriptional outcomes.

Tissue-Specific Effects of Leptin on Glucose and Lipid Metabolism

The discovery of leptin was intrinsically associated with its ability to regulate body weight. However, the effects of leptin are more far-reaching and include profound glucose-lowering and anti-lipogenic effects, independent of leptin’s regulation of body weight. Regulation of glucose metabolism by leptin is mediated both centrally and via peripheral tissues and is influenced by the activation status of insulin signaling pathways. Ectopic fat accumulation is diminished by both central and peripheral leptin, an effect that is beneficial in obesity-associated disorders. The magnitude of leptin action depends upon the tissue, sex, and context being examined. Peripheral tissues that are of particular relevance include the endocrine pancreas, liver, skeletal muscle, adipose tissues, immune cells, and the cardiovascular system. As a result of its potent metabolic activity, leptin is used to control hyperglycemia in patients with lipodystrophy and is being explored as an adjunct to insulin in patients with type 1 diabetes. To fully understand the role of leptin in physiology and to maximize its therapeutic potential, the mechanisms of leptin action in these tissues needs to be further explored.

Obesity and Bone

Obesity and osteoporosis are both common conditions with high rates of morbidity and mortality. There is a relationship between obesity and bone. There are multiple factors that influence the risk of fracture, including the quality of bone, the risk of falls, and the padding around the bone. These multiple factors partly explain the finding that obesity protects against fractures in some sites while increasing the risk in other parts of the body. While it is well known that increased weight builds bone, there are several mechanisms related to the obese state that make the bone more fragile. These include the increased production of bone marrow fat cells at the expense of bone-forming osteoblasts, an increase in inflammatory cytokines leading to the activation of bone-resorbing osteoclasts, mutations in the FTO gene, and obesity-induced increased osteoblast senescence. Surprisingly, the relationship between bone and obesity is not unidirectional; there is now evidence that osteocytes are able to regulate body weight by acting as weighing machines.

Postpartum Physical Activity and Weight Retention within One Year: A Prospective Cohort Study in Vietnam

After delivery, mothers are encouraged to increase physical activity (PA) gradually to regulate body weight; however, data on PA in relation to postpartum weight retention remains scarce, particularly among Asian women. In a cohort of 1617 Vietnamese mothers, we investigated the prospective association between habitual PA exposures at 3-month postpartum and weight retention at 6-month and 12-month postpartum. Detailed information on PA intensity and domains was collected from participants using a validated instrument specifically for Vietnamese women. Linear regression analyses and a general linear model for the repeated weight retention measures were used to ascertain the apparent relationships. On average, the participants reported 3.6 (SD 3.9) and 2.6 (SD 3.8) kg weight loss at 6- and 12-month postpartum, respectively. Total and light-intensity PA were inversely associated with the postpartum weight retention (p for trend <0.05). Our findings highlight the importance of resuming PA in the early postpartum period as an appropriate weight management strategy.

The role of orexin in controlling the activity of the adipo-pancreatic axis

Orexin A and B are two neuropeptides, which regulate a variety of physiological functions by interacting with central nervous system and peripheral tissues. Biological effects of orexins are mediated through two G-protein-coupled receptors (OXR1 and OXR2). In addition to their strong influence on the sleep–wake cycle, there is growing evidence that orexins regulate body weight, glucose homeostasis and insulin sensitivity. Furthermore, orexins promote energy expenditure and protect against obesity by interacting with brown adipocytes. Fat tissue and the endocrine pancreas play pivotal roles in maintaining energy homeostasis. Since both organs are crucially important in the context of pathophysiology of obesity and diabetes, we summarize the current knowledge regarding the role of orexins and their receptors in controlling adipocytes as well as the endocrine pancreatic functions. Particularly, we discuss studies evaluating the effects of orexins in controlling brown and white adipocytes as well as pancreatic alpha and beta cell functions.

Inducible Neuronal Inactivation of Sim1 in Adult Mice Causes Hyperphagic Obesity

Germline haploinsufficiency of human or mouse Sim1 is associated with hyperphagic obesity. Sim1 encodes a transcription factor required for proper formation of the paraventricular (PVN), supraoptic, and anterior periventricular hypothalamic nuclei. Sim1 expression persists in these neurons in adult mice, raising the question of whether it plays a physiologic role in regulation of energy balance. We previously showed that Sim1 heterozygous mice had normal numbers of PVN neurons that were hyporesponsive to melanocortin 4 receptor agonism and showed reduced oxytocin expression. Furthermore, conditional postnatal neuronal inactivation of Sim1 also caused hyperphagic obesity and decreased hypothalamic oxytocin expression. PVN projections to the hindbrain, where oxytocin is thought to act to modulate satiety, were anatomically intact in both Sim1 heterozygous and conditional knockout mice. These experiments provided evidence that Sim1 functions in energy balance apart from its role in hypothalamic development but did not rule out effects of Sim1 deficiency on postnatal hypothalamic maturation. To address this possibility, we used a tamoxifen-inducible, neural-specific Cre transgene to conditionally inactivate Sim1 in adult mice with mature hypothalamic circuitry. Induced Sim1 inactivation caused increased food and water intake and decreased expression of PVN neuropeptides, especially oxytocin and vasopressin, with no change in energy expenditure. Sim1 expression was not required for survival of PVN neurons. The results corroborate previous evidence that Sim1 acts physiologically as well as developmentally to regulate body weight. Inducible knockout mice provide a system for studying Sim1’s physiologic function in energy balance and identifying its relevant transcriptional targets in the hypothalamus.