Browsing by Subject "leptin"

Now showing 1 - 4 of 4
  • Thumbnail Image
    Item
    Cilia Associated Signaling in Adult Energy Homeostasis
    (2022-05) Bansal, Ruchi; Berbari, Nicolas F.; Perrin, Benjamin J.; Mastracci, Teresa L.; Baucum, Anthony J.; Dunn, Kenneth W.
    Primary cilia are solitary cellular appendages that function as signaling centers for cells in adult energy homeostasis. Here in chapter 1, I introduce cilia and how dysfunction of these conserved organelles results in ciliopathies, such as Bardet-Biedl Syndrome (BBS), which present with childhood obesity. Furthermore, conditional loss of primary cilia from neurons in the hypothalamus leads to hyperphagia and obesity in mouse models of ciliopathies. Classically, cilia coordinate signaling often through specific G-protein coupled receptors (GPCRs) as is the case in both vision and olfaction. In addition, neurons throughout the brain including hypothalamic neurons possess primary cilia whose dysfunction contributes to ciliopathy-associated obesity. How neuronal cilia regulate the signaling of GPCRs remains unclear and many fundamental cell biology questions remain about cilia mediated signaling. For example, how cilia coordinate signaling to influence neuronal activity is unknown. To begin to address some of these cell biology questions around neuronal cilia, chapter 2, describes the development and use of a system for primary neuronal cultures from the hypothalamus. Using this system, we found that activation of the cilia regulated hedgehog pathway, which is critical in development, influenced the ability of neurons to respond to GPCR ligands. This result highlights the role of the developmentally critical hedgehog pathway on terminally differentiated hypothalamic neurons. One challenge facing the cilia field is our ability to assess cilia in large numbers without potential bias. This is especially true in tissues like the brain, where cilia appear to have region-specific characteristics. Work included in Chapter 3 describes the use of a computer-assisted artificial intelligence (Ai) approach to analyze cilia composition and morphology in a less biased and high throughput manner. Cilia length and intensities are important parameters for evaluation of cilia signaling. Evidence suggests that activation of some ciliary GPCRs results in shortening of cilia whereas deviations from normal cilia length in mutant phenotypes affects normal physiological processes such as decreased mucociliary clearance. Therefore, to analyze a large number of cilia, we describe the use of the Ai module from in vitro and in vivo samples in a reproducible manner that minimizes user bias. Using this approach, we identified that Mchr1 expression is significantly stronger in the cilia of paraventricular nucleus than that in the arcuate nucleus of adult mice. Work in Chapter 4 continues to explore the integration between hedgehog pathway and ciliary GPCR signaling in the central nervous system, and its relevance with energy homeostasis. We evaluated the hedgehog ligand in the plasma of mice in acute and long-term metabolic changes and identified that the activity of the ligand changed under altered metabolic conditions. We also developed a genetic mouse model where hedgehog signaling was constitutively active in neuronal cilia. These mice become hyperphagic and obese. These results further emphasize the potential role of the hedgehog signaling pathway in regulation of feeding behavior in adult vertebrates. Overall, results from this work will provide a better understanding of the defects not only underlying ciliopathy-associated obesity but may also reveal more common mechanisms of centrally mediated obesity. In addition, the tools I have developed will help in understanding how neuronal cilia are used for intercellular communications and ultimately how they regulate behaviors like feeding.
  • Thumbnail Image
    Item
    Effect of Depression Treatment on Somatic Depressive Symptoms and Cardiometabolic Biomarkers among People without Diabetes
    (2022-05) Shell, Aubrey Lynn; Stewart, Jesse; Hirsh, Adam; Cyders, Melissa; Considine, Robert
    While depression is a risk factor for type 2 diabetes, little is known about the effect of depression treatment on diabetes risk markers. Using data from the recently completed eIMPACT trial (NCT02458690, supported by R01 HL122245), I examined if depression intervention improves diabetes risk markers and if improvements in somatic depressive symptoms mediate potential intervention effects. 216 participants (primary care patients ≥50 years with depression and elevated cardiovascular disease risk from a safety net healthcare system) were randomized to 12 months of the eIMPACT intervention (modernized collaborative care intervention involving internet cognitive-behavioral therapy [CBT], telephonic CBT, and/or select antidepressants; n=107) or usual primary care for depression (primary care providers supported by embedded behavioral health clinicians and affiliated psychiatrists; n = 109). Given my focus on diabetes risk, I excluded participants who did not attend the post-treatment visit (n = 17) or who had a diabetes history at pre-treatment (n = 73), leaving a final sample of 126 (n=66 intervention, n=60 usual care; Mage = 58 years, 79% women, 50% Black, 47% with income <$10k/year). I computed depressive symptom severity variables from the Hopkins Symptom Checklist-20 (SCL-20) items: hyperphagia (“overeating” item), poor appetite (“poor appetite”), hypersomnia (“sleeping too much”), disturbed sleep (“sleep that is restless or disturbed”) and SCL-15 (mean of items not pertaining to appetite or sleep). I calculated insulin resistance from fasting plasma glucose and insulin using the Homeostasis Model Assessment for Insulin Resistance (HOMA-IR)-2 calculator, body mass index (BMI) from measured height and weight, and plasma concentrations of high-sensitivity C-reactive protein (hsCRP), leptin, and ghrelin using ELISA kits. Parallel mediation analyses revealed that 12 months of modernized collaborative care for depression improved both directions of sleep symptoms but did not improve poor appetite or hyperphagia – the somatic symptom most consistently linked with increases in HOMA-IR, BMI, hsCRP, and leptin. Of the five cardiometabolic biomarkers examined, the eIMPACT intervention decreased only hsCRP and ghrelin. There were no intervention effects on HOMA-IR, BMI, or leptin. In addition, no somatic depressive symptoms mediated intervention effects on the cardiometabolic biomarkers, nor did race moderate any mediation effects. Further research is warranted to determine best practices for targeting hyperphagia and reducing cardiometabolic disease risk among people with depression.
  • Thumbnail Image
    Item
    Leptin augments coronary vasoconstriction and smooth muscle proliferation via a Rho kinase dependent pathway
    (Springer, 2016-05) Noblet, Jillian N.; Goodwill, Adam G.; Sassoon, Daniel J.; Kiel, Alexander M.; Tune, Johnathan D.; Department of Cellular & Integrative Physiology, IU School of Medicine
    Leptin has been implicated as a key upstream mediator of pathways associated with coronary vascular dysfunction and disease. The purpose of this investigation was to test the hypothesis that leptin modifies the coronary artery proteome and promotes increases in coronary smooth muscle contraction and proliferation via influences on Rho kinase signaling. Global proteomic assessment of coronary arteries from lean swine cultured with obese concentrations of leptin (30 ng/mL) for 3 days revealed significant alterations in the coronary artery proteome (68 proteins) and identified an association between leptin treatment and calcium signaling/contraction (four proteins) and cellular growth and proliferation (35 proteins). Isometric tension studies demonstrated that both acute (30 min) and chronic (3 days, serum-free media) exposure to obese concentrations of leptin potentiated depolarization-induced contraction of coronary arteries. Inhibition of Rho kinase significantly reduced leptin-mediated increases in coronary artery contractions. The effects of leptin on the functional expression of Rho kinase were time-dependent, as acute treatment increased Rho kinase activity while chronic (3 day) exposure was associated with increases in Rho kinase protein abundance. Proliferation assays following chronic leptin administration (8 day, serum-containing media) demonstrated that leptin augmented coronary vascular smooth muscle proliferation and increased Rho kinase activity. Inhibition of Rho kinase significantly reduced these effects of leptin. Taken together, these findings demonstrate that leptin promotes increases in coronary vasoconstriction and smooth muscle proliferation and indicate that these phenotypic effects are associated with alterations in the coronary artery proteome and dynamic effects on the Rho kinase pathway.
  • Thumbnail Image
    Item
    Role for Leptin and Leptin Receptors in Stem Cells During Health and Diseases
    (Springer, 2021) Trinh, Thao; Broxmeyer, Hal E.; Microbiology and Immunology, School of Medicine
    Hematopoietic stem cells (HSCs) give rise to all blood and immune cells in the body. These rare cells reside in the hypoxic niche of the bone marrow (BM) where they are subjected to a complex network of regulatory factors including cellular and molecular components. To sustain hematopoiesis over the lifetime of an individual, HSCs maintain distinctive metabolic programs, and in recent years nutritional factors have been increasingly recognized as critical regulators of HSC numbers and functions. Leptin (LEP), a neuroendocrine messenger, and its receptor (LEPR) are well-known for their immunomodulatory and energy balancing effects; yet, how LEP/LEPR signaling plays a role in hematopoiesis is under-appreciated. In this review, we summarize and highlight recent work that demonstrated involvement of LEP/LEPR in hematopoiesis under steady state or stress-associated situations as well as in pathological conditions such as cardiovascular diseases and malignancies. Although the field is only in its infancy, these studies suggest evidence of potential clinical applications and proof-of-principle for more in-depth future research.