International Journal of Molecular Sciences

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20 pages, 3729 KiB

Open AccessArticle

Malic Enzyme 1 (ME1) Promotes Adiposity and Hepatic Steatosis and Induces Circulating Insulin and Leptin in Obese Female Mice

by Frank A. Simmen, John Mark P. Pabona, Ahmed Al-Dwairi, Iad Alhallak, Maria Theresa E. Montales and Rosalia C. M. Simmen

Int. J. Mol. Sci. 2023, 24(7), 6613; https://doi.org/10.3390/ijms24076613 - 1 Apr 2023

Cited by 5 | Viewed by 2129

Abstract

Malic Enzyme 1 (ME1) supports lipogenesis, cholesterol synthesis, and cellular redox potential by catalyzing the decarboxylation of L-malate to pyruvate, and the concomitant reduction of NADP to NADPH. We examined the contribution of ME1 to the development of obesity by provision of an [...] Read more.

Malic Enzyme 1 (ME1) supports lipogenesis, cholesterol synthesis, and cellular redox potential by catalyzing the decarboxylation of L-malate to pyruvate, and the concomitant reduction of NADP to NADPH. We examined the contribution of ME1 to the development of obesity by provision of an obesogenic diet to C57BL/6 wild type (WT) and MOD-1 (lack ME1 protein) female mice. Adiposity, serum hormone levels, and adipose, mammary gland, liver, and small intestine gene expression patterns were compared between experimental groups after 10 weeks on a diet. Relative to WT female mice, MOD-1 female mice exhibited lower body weights and less adiposity; decreased concentrations of insulin, leptin, and estrogen; higher concentrations of adiponectin and progesterone; smaller-sized mammary gland adipocytes; and reduced hepatosteatosis. MOD-1 mice had diminished expression of Lep gene in abdominal fat; Lep, Pparg, Klf9, and Acaca genes in mammary glands; Pparg and Cdkn1a genes in liver; and Tlr9 and Ffar3 genes in the small intestine. By contrast, liver expression of Cdkn2a and Lepr genes was augmented in MOD-1, relative to WT mice. Results document an integrative role for ME1 in development of female obesity, suggest novel linkages with specific pathways/genes, and further support the therapeutic targeting of ME1 for obesity, diabetes, and fatty liver disease. Full article

(This article belongs to the Special Issue Hormone Signaling in Human Health and Diseases)

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16 pages, 4489 KiB

Open AccessArticle

Muscle Cell Insulin Resistance Is Attenuated by Rosmarinic Acid: Elucidating the Mechanisms Involved

by Danja J. Den Hartogh, Filip Vlavcheski and Evangelia Tsiani

Int. J. Mol. Sci. 2023, 24(6), 5094; https://doi.org/10.3390/ijms24065094 - 7 Mar 2023

Cited by 2 | Viewed by 1616

Abstract

Obesity and elevated blood free fatty acid (FFA) levels lead to impaired insulin action causing insulin resistance in skeletal muscle, and contributing to the development of type 2 diabetes mellitus (T2DM). Mechanistically, insulin resistance is associated with increased serine phosphorylation of the insulin [...] Read more.

Obesity and elevated blood free fatty acid (FFA) levels lead to impaired insulin action causing insulin resistance in skeletal muscle, and contributing to the development of type 2 diabetes mellitus (T2DM). Mechanistically, insulin resistance is associated with increased serine phosphorylation of the insulin receptor substrate (IRS) mediated by serine/threonine kinases including mTOR and p70S6K. Evidence demonstrated that activation of the energy sensor AMP-activated protein kinase (AMPK) may be an attractive target to counteract insulin resistance. We reported previously that rosemary extract (RE) and the RE polyphenol carnosic acid (CA) activated AMPK and counteracted the FFA-induced insulin resistance in muscle cells. The effect of rosmarinic acid (RA), another polyphenolic constituent of RE, on FFA-induced muscle insulin resistance has never been examined and is the focus of the current study. Muscle cell (L6) exposure to FFA palmitate resulted in increased serine phosphorylation of IRS-1 and reduced insulin-mediated (i) Akt activation, (ii) GLUT4 glucose transporter translocation, and (iii) glucose uptake. Notably, RA treatment abolished these effects, and restored the insulin-stimulated glucose uptake. Palmitate treatment increased the phosphorylation/activation of mTOR and p70S6K, kinases known to be involved in insulin resistance and RA significantly reduced these effects. RA increased the phosphorylation of AMPK, even in the presence of palmitate. Our data indicate that RA has the potential to counteract the palmitate-induced insulin resistance in muscle cells, and further studies are required to explore its antidiabetic properties. Full article

(This article belongs to the Special Issue Hormone Signaling in Human Health and Diseases)

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26 pages, 6044 KiB

Open AccessArticle

NFκB-Mediated Mechanisms Drive PEDF Expression and Function in Pre- and Post-Menopausal Oestrogen Levels in Breast Cancer

by Naomi Brook, Jespal Gill, Arun Dharmarajan, Arlene Chan and Crispin R. Dass

Int. J. Mol. Sci. 2022, 23(24), 15641; https://doi.org/10.3390/ijms232415641 - 9 Dec 2022

Cited by 4 | Viewed by 1772

Abstract

Pigment epithelium-derived factor (PEDF) protein regulates normal bone, with anti-tumour roles in bone and breast cancer (BC). Pre- and post-menopausal oestrogen levels may regulate PEDF expression and function in BC, though the mechanisms behind this remain unknown. In this study, in vitro models [...] Read more.

Pigment epithelium-derived factor (PEDF) protein regulates normal bone, with anti-tumour roles in bone and breast cancer (BC). Pre- and post-menopausal oestrogen levels may regulate PEDF expression and function in BC, though the mechanisms behind this remain unknown. In this study, in vitro models simulating pre- and post-menopausal bone microenvironments were used to evaluate if PEDF regulates pro-metastatic biomarker expression and downstream functional effects on BC cells. PEDF treatment reduced phosphorylated-nuclear factor-κB p65 subunit (p-NFκB-p65), tumour necrosis factor-α (TNFα), C-X-C chemokine receptor type-4 (CXCR4), and urokinase plasminogen activator receptor (uPAR) in oestrogen receptor (ER)+/human epidermal growth factor receptor-2 (HER2)- BC cells under post-menopausal oestrogen conditions. In triple negative BC (TNBC) cells, PEDF treatment reduced pNFκB-p65 and uPAR expression under pre-menopausal oestrogen conditions. A potential reciprocal regulatory axis between p-NFκB-65 and PEDF in BC was identified, which was BC subtype-specific and differentially regulated by menopausal oestrogen conditions. The effects of PEDF treatment and NFκB inhibition on BC cell function under menopausal conditions were also compared. PEDF treatment exhibited superior anti-viability effects, while combined PEDF and NFκB-p65 inhibitor treatment was superior in reducing BC cell colony formation in a subtype-specific manner. Lastly, immunohistochemical evaluation of p-NFκB-p65 and PEDF expression in human BC and bone metastases specimens revealed an inverse correlation between nuclear PEDF and NFκB expression in bone metastases. We propose that menopausal status is associated with a PEDF/NFκB reciprocal regulatory axis, which drives PEDF expression and anti-metastatic function in a subtype-specific manner. Altogether, our findings identify pre-menopausal TNBC and post-menopausal ER+/HER2- BC patients as target populations for future PEDF research. Full article

(This article belongs to the Special Issue Hormone Signaling in Human Health and Diseases)

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13 pages, 1153 KiB

Open AccessCommunication

Sleep and Anabolic/Catabolic Hormonal Profile in Sedentary Middle-Aged Adults: The FIT-AGEING Study

by Sol Mochón-Benguigui, Almudena Carneiro-Barrera, Manuel Dote-Montero, Manuel J. Castillo and Francisco J. Amaro-Gahete

Int. J. Mol. Sci. 2022, 23(23), 14709; https://doi.org/10.3390/ijms232314709 - 25 Nov 2022

Cited by 2 | Viewed by 1933

Abstract

Sleep quality plays an important role in the modulation of several aging markers. This influence could be explained by aging-induced hormonal changes. Indeed, poor sleep quality has been associated with the development of several endocrine-related health complications. This study examined the relationship of [...] Read more.

Sleep quality plays an important role in the modulation of several aging markers. This influence could be explained by aging-induced hormonal changes. Indeed, poor sleep quality has been associated with the development of several endocrine-related health complications. This study examined the relationship of both subjective and objective sleep quantity and quality, with basal levels of selected plasma anabolic and catabolic hormones in sedentary middle-aged adults. A total of 74 volunteers (52.7% women; aged 53.7 ± 5.1) were recruited for this study. Subjective sleep quality was assessed by the Pittsburgh Sleep Quality Index (PSQI; higher scores indicate worse sleep quality), and objective sleep quality parameters (total sleep time [TST], wake after sleep onset [WASO], and sleep efficiency [SE]) were measured using a wrist-worn accelerometer. Basal levels of plasma dehydroepiandrosterone sulphate (DHEAS), total testosterone, sex hormone binding globulin (SHBG), somatotropin, and cortisol levels, were determined. Free testosterone was calculated from the total testosterone and SHBG levels. No associations of global PSQI score, TST, WASO, and SE with DHEAS, free testosterone, and somatotropin plasma levels were found, neither in men nor in women (all p ≥ 0.05). Global PSQI score was inversely related to cortisol plasma levels in women (p = 0.043). WASO was positively associated with cortisol plasma levels, while SE was negatively associated with cortisol plasma levels in women (all p ≤ 0.027). Sleep quality is not related to levels of plasma anabolic hormones, but to levels of catabolic hormones, in sedentary middle-aged adults. Therefore, these results suggest that potential changes in aging biomarkers associated with sleep disturbances, could be mediated by age-related changes in the catabolic endocrine system. Full article

(This article belongs to the Special Issue Hormone Signaling in Human Health and Diseases)

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Review

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19 pages, 1772 KiB

Open AccessReview

Role of Sex Hormones in Prevalent Kidney Diseases

by Carolina Conte, Giulia Antonelli, Maria Elena Melica, Mirko Tarocchi, Paola Romagnani and Anna Julie Peired

Int. J. Mol. Sci. 2023, 24(9), 8244; https://doi.org/10.3390/ijms24098244 - 4 May 2023

Cited by 9 | Viewed by 2991

Abstract

Chronic kidney disease (CKD) is a constantly growing global health burden, with more than 840 million people affected worldwide. CKD presents sex disparities in the pathophysiology of the disease, as well as in the epidemiology, clinical manifestations, and disease progression. Overall, while CKD [...] Read more.

Chronic kidney disease (CKD) is a constantly growing global health burden, with more than 840 million people affected worldwide. CKD presents sex disparities in the pathophysiology of the disease, as well as in the epidemiology, clinical manifestations, and disease progression. Overall, while CKD is more frequent in females, males have a higher risk to progress to end-stage kidney disease. In recent years, numerous studies have highlighted the role of sex hormones in the health and diseases of several organs, including the kidney. In this review, we present a clinical overview of the sex-differences in CKD and a selection of prominent kidney diseases causing CKD: lupus nephritis, diabetic kidney disease, IgA nephropathy, and autosomal dominant polycystic kidney disease. We report clinical and experimental findings on the role of sex hormones in the development of the disease and its progression to end-stage kidney disease. Full article

(This article belongs to the Special Issue Hormone Signaling in Human Health and Diseases)

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14 pages, 719 KiB

Open AccessReview

The Expression of Insulin in the Central Nervous System: What Have We Learned So Far?

by Tamara Dakic, Tanja Jevdjovic, Iva Lakic, Aleksandra Ruzicic, Nebojsa Jasnic, Sinisa Djurasevic, Jelena Djordjevic and Predrag Vujovic

Int. J. Mol. Sci. 2023, 24(7), 6586; https://doi.org/10.3390/ijms24076586 - 1 Apr 2023

Cited by 5 | Viewed by 4546

Abstract

After being discovered over a century ago, insulin was long considered to be a hormone exclusively produced by the pancreas. Insulin presence was later discovered in the brain, which was originally accounted for by its transport across the blood-brain barrier. Considering that both [...] Read more.

After being discovered over a century ago, insulin was long considered to be a hormone exclusively produced by the pancreas. Insulin presence was later discovered in the brain, which was originally accounted for by its transport across the blood-brain barrier. Considering that both insulin mRNA and insulin were detected in the central nervous system (CNS), it is now known that this hormone is also synthesized in several brain regions, including the hypothalamus, hippocampus, cerebral and cerebellar cortex, and olfactory bulb. Although many roles of insulin in the CNS have been described, it was initially unknown which of them could be attributed to brain-derived and which to pancreatic insulin or whether their actions in the brain overlap. However, more and more studies have been emerging lately, focusing solely on the roles of brain-derived insulin. The aim of this review was to present the latest findings on the roles of brain-derived insulin, including neuroprotection, control of growth hormone secretion, and regulation of appetite and neuronal glucose uptake. Lastly, the impairment of signaling initiated by brain-derived insulin was addressed in regard to memory decline in humans. Full article

(This article belongs to the Special Issue Hormone Signaling in Human Health and Diseases)

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27 pages, 5578 KiB

Open AccessReview

The Hypothalamic-Pituitary-Gonadal Axis in Men with Schizophrenia

by Agnieszka Matuszewska, Krzysztof Kowalski, Paulina Jawień, Tomasz Tomkalski, Dagmara Gaweł-Dąbrowska, Anna Merwid-Ląd, Ewa Szeląg, Karolina Błaszczak, Benita Wiatrak, Maciej Danielewski, Janusz Piasny and Adam Szeląg

Int. J. Mol. Sci. 2023, 24(7), 6492; https://doi.org/10.3390/ijms24076492 - 30 Mar 2023

Cited by 6 | Viewed by 7466

Abstract

Schizophrenia is a severe mental disorder with a chronic, progressive course. The etiology of this condition is linked to the interactions of multiple genes and environmental factors. The earlier age of onset of schizophrenia, the higher frequency of negative symptoms in the clinical [...] Read more.

Schizophrenia is a severe mental disorder with a chronic, progressive course. The etiology of this condition is linked to the interactions of multiple genes and environmental factors. The earlier age of onset of schizophrenia, the higher frequency of negative symptoms in the clinical presentation, and the poorer response to antipsychotic treatment in men compared to women suggests the involvement of sex hormones in these processes. This article aims to draw attention to the possible relationship between testosterone and some clinical features in male schizophrenic patients and discuss the complex nature of these phenomena based on data from the literature. PubMed, Web of Science, and Google Scholar databases were searched to select the papers without limiting the time of the publications. Hormone levels in the body are regulated by many organs and systems, and take place through the neuroendocrine, hormonal, neural, and metabolic pathways. Sex hormones play an important role in the development and function of the organism. Besides their impact on secondary sex characteristics, they influence brain development and function, mood, and cognition. In men with schizophrenia, altered testosterone levels were noted. In many cases, evidence from available single studies gave contradictory results. However, it seems that the testosterone level in men affected by schizophrenia may differ depending on the phase of the disease, types of clinical symptoms, and administered therapy. The etiology of testosterone level disturbances may be very complex. Besides the impact of the illness (schizophrenia), stress, and antipsychotic drug-induced hyperprolactinemia, testosterone levels may be influenced by, i.a., obesity, substances of abuse (e.g., ethanol), or liver damage. Full article

(This article belongs to the Special Issue Hormone Signaling in Human Health and Diseases)

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27 pages, 1022 KiB

Open AccessReview

The Impact of Physical Exercise on the Circulating Levels of BDNF and NT 4/5: A Review

by Daniel Ribeiro, Luca Petrigna, Frederico C. Pereira, Antonella Muscella, Antonino Bianco and Paula Tavares

Int. J. Mol. Sci. 2021, 22(16), 8814; https://doi.org/10.3390/ijms22168814 - 16 Aug 2021

Cited by 21 | Viewed by 4377

Abstract

(1) Background: One mechanism through which physical activity (PA) provides benefits is by triggering activity at a molecular level, where neurotrophins (NTs) are known to play an important role. However, the expression of the circulating levels of neurotrophic factors, brain-derived neurotrophic factor (BDNF) [...] Read more.

(1) Background: One mechanism through which physical activity (PA) provides benefits is by triggering activity at a molecular level, where neurotrophins (NTs) are known to play an important role. However, the expression of the circulating levels of neurotrophic factors, brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT-4/5), in response to exercise, is not fully understood. Therefore, the aim was to provide an updated overview on the neurotrophin (NT) variation levels of BDNF and NT-4/5 as a consequence of a long-term aerobic exercise intervention, and to understand and describe whether the upregulation of circulating NT levels is a result of neurotrophic factors produced and released from the brain, and/or from neurotrophic secreting peripheral organs. (2) Methods: The articles were collected from PubMed, SPORTDiscus, Web of Science, MEDLINE, and Embase. Data were analyzed through a narrative synthesis. (3) Results: 30 articles studied humans who performed training protocols that ranged from 4 to 48 weeks; 22 articles studied rodents with an intervention period that ranged from 4 to 64 weeks. (4) Conclusions: There is no unanimity between the upregulation of BDNF in humans; conversely, concerning both BDNF and NT-4/5 in animal models, the results are heterogeneous. Whilst BDNF upregulation appears to be in relative agreement, NT-4/5 seems to display contradictory and inconsistent conclusions. Full article

(This article belongs to the Special Issue Hormone Signaling in Human Health and Diseases)

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