Sex differences in metabolic pathways are regulated by Pfkfb3 and Pdk4 expression in rodent muscle

AbstractSkeletal muscles display sexually dimorphic features. Biochemically, glycolysis and fatty acid β-oxidation occur preferentially in the muscles of males and females, respectively. However, the mechanisms of the selective utilization of these fuels remains elusive. Here, we obtain transcriptomes from quadriceps type IIB fibers of untreated, gonadectomized, and sex steroid-treated mice of both sexes. Analyses of the transcriptomes unveil two genes, Pfkfb3 (phosphofructokinase-2) and Pdk4 (pyruvate dehydrogenase kinase 4), that may function as switches between the two sexually dimorphic metabolic pathways. Interestingly, Pfkfb3 and Pdk4 show male-enriched and estradiol-enhanced expression, respectively. Moreover, the contribution of these genes to sexually dimorphic metabolism is demonstrated by knockdown studies with cultured type IIB muscle fibers. Considering that skeletal muscles as a whole are the largest energy-consuming organs, our results provide insights into energy metabolism in the two sexes, during the estrus cycle in women, and under pathological conditions involving skeletal muscles.

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Genetic Perturbation of Pyruvate Dehydrogenase Kinase 1 Modulates Growth, Angiogenesis and Metabolic Pathways in Ovarian Cancer Xenografts

Cells ◽

10.3390/cells10020325 ◽

2021 ◽

Vol 10 (2) ◽

pp. 325

Author(s):

Carolina Venturoli ◽

Ilaria Piga ◽

Matteo Curtarello ◽

Martina Verza ◽

Giovanni Esposito ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Pyruvate Dehydrogenase ◽

Metabolic Pathways ◽

Negative Impact ◽

Digital Pathology ◽

Pyruvate Dehydrogenase Kinase ◽

Ovarian Cancer Cells ◽

Pyruvate Dehydrogenase Kinase 1

Pyruvate dehydrogenase kinase 1 (PDK1) blockade triggers are well characterized in vitro metabolic alterations in cancer cells, including reduced glycolysis and increased glucose oxidation. Here, by gene expression profiling and digital pathology-mediated quantification of in situ markers in tumors, we investigated effects of PDK1 silencing on growth, angiogenesis and metabolic features of tumor xenografts formed by highly glycolytic OC316 and OVCAR3 ovarian cancer cells. Notably, at variance with the moderate antiproliferative effects observed in vitro, we found a dramatic negative impact of PDK1 silencing on tumor growth. These findings were associated with reduced angiogenesis and increased necrosis in the OC316 and OVCAR3 tumor models, respectively. Analysis of viable tumor areas uncovered increased proliferation as well as increased apoptosis in PDK1-silenced OVCAR3 tumors. Moreover, RNA profiling disclosed increased glucose catabolic pathways—comprising both oxidative phosphorylation and glycolysis—in PDK1-silenced OVCAR3 tumors, in line with the high mitotic activity detected in the viable rim of these tumors. Altogether, our findings add new evidence in support of a link between tumor metabolism and angiogenesis and remark on the importance of investigating net effects of modulations of metabolic pathways in the context of the tumor microenvironment.

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Activation of Liver X Receptor Regulates Substrate Oxidation in White Adipocytes

Endocrinology ◽

10.1210/en.2009-0676 ◽

2009 ◽

Vol 150 (9) ◽

pp. 4104-4113 ◽

Cited By ~ 36

Author(s):

Britta M. Stenson ◽

Mikael Rydén ◽

Knut R. Steffensen ◽

Kerstin Wåhlén ◽

Amanda T. Pettersson ◽

...

Keyword(s):

Pyruvate Dehydrogenase ◽

Pyruvate Dehydrogenase Complex ◽

Substrate Oxidation ◽

Pyruvate Dehydrogenase Kinase ◽

Tissue Mass ◽

Metabolic Complications ◽

Pyruvate Dehydrogenase Kinase 4 ◽

White Adipocytes ◽

X Receptors

Abstract Liver X receptors (LXRs) are nuclear receptors with established roles in cholesterol, lipid, and carbohydrate metabolism, although their function in adipocytes is not well characterized. Increased adipose tissue mass in obesity is associated with increased adipocyte lipolysis. Fatty acids (FA) generated by lipolysis can be oxidized by mitochondrial β-oxidation, reesterified, or released from the adipocyte. The latter results in higher circulating levels of free FAs, in turn causing obesity-related metabolic complications. However, mitochondrial β-oxidation can at least in part counteract an increased output of FA into circulation. In this study, we provide evidence that activation of LXRs up-regulates mitochondrial β-oxidation in both human and murine white adipocytes. We also show that the expression of a kinase regulating the cellular fuel switch, pyruvate dehydrogenase kinase 4 (PDK4), is up-regulated by the LXR agonist GW3965 in both in vitro differentiated human primary adipocytes and differentiated murine 3T3-L1 cells. Moreover, activation of LXR causes PDK4-dependent phosphorylation of the pyruvate dehydrogenase complex, thereby decreasing its activity and attenuating glucose oxidation. The specificity of the GW3965 effect on oxidation was confirmed by RNA interference targeting LXRs. We propose that LXR has an important role in the regulation of substrate oxidation and the switch between lipids and carbohydrates as cellular fuel in both human and murine white adipocytes.

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Sex differences in melanotic encapsulation responses (immunocompetence) in the damselfly Lestes forcipatus Rambur

Canadian Journal of Zoology ◽

10.1139/z02-159 ◽

2002 ◽

Vol 80 (9) ◽

pp. 1578-1583 ◽

Cited By ~ 28

Author(s):

Christopher P Yourth ◽

Mark R Forbes ◽

Robert L Baker

Keyword(s):

Sex Differences ◽

Immune Responses ◽

Life Histories ◽

Mass Gain ◽

Sexually Dimorphic ◽

Foreign Objects ◽

Males And Females ◽

And Gender ◽

Parasitic Mites ◽

Melanotic Encapsulation

A few studies have shown that male and female invertebrates differ in immunity and that these differences appear related to differences in sexual dimorphism and gender differences in life histories. Melanotic encapsulation of foreign objects in insects is one form of immunity. The damselfly Lestes forcipatus Rambur is moderately sexually dimorphic, and much is known about patterns of mass gain in congeners relating to differences in life history between males and females. In this study, females were more immunoresponsive than males under controlled temperatures, following emergence, and at a time when parasitic mites were challenging these hosts. However, males and females that overlapped in mass at emergence did not differ in their immune responses. Males in better condition at emergence were more immunoresponsive than lighter males, but this relation was not found in females. Sex differences in immune expression may have implications for how females versus males are able to deal with challenges from parasites, under varying environmental conditions.

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Transforming Growth Factor β Mediates Drug Resistance by Regulating the Expression of Pyruvate Dehydrogenase Kinase 4 in Colorectal Cancer

Journal of Biological Chemistry ◽

10.1074/jbc.m116.713735 ◽

2016 ◽

Vol 291 (33) ◽

pp. 17405-17416 ◽

Cited By ~ 24

Author(s):

Yang Zhang ◽

Yi Zhang ◽

Liying Geng ◽

Haowei Yi ◽

Wei Huo ◽

...

Keyword(s):

Colorectal Cancer ◽

Colon Cancer ◽

Drug Resistance ◽

Cancer Cells ◽

Pyruvate Dehydrogenase ◽

Pyruvate Dehydrogenase Kinase ◽

Dependent Manner ◽

Colon Cancer Cells ◽

Pyruvate Dehydrogenase Kinase 4 ◽

Mouse Xenograft Model

Drug resistance is one of the main causes of colon cancer recurrence. However, our understanding of the underlying mechanisms and availability of therapeutic options remains limited. Here we show that expression of pyruvate dehydrogenase kinase 4 (PDK4) is positively correlated with drug resistance of colon cancer cells and induced by 5-fluorouracil (5-FU) treatment in drug-resistant but not drug-sensitive cells. Knockdown of PDK4 expression sensitizes colon cancer cells to 5-FU or oxaliplatin-induced apoptosis in vitro and increases the effectiveness of 5-FU in the inhibition of tumor growth in a mouse xenograft model in vivo. In addition, we demonstrate for the first time that TGFβ mediates drug resistance by regulating PDK4 expression and that 5-FU induces PDK4 expression in a TGFβ signaling-dependent manner. Mechanistically, knockdown or inhibition of PDK4 significantly increases the inhibitory effect of 5-FU on expression of the anti-apoptotic factors Bcl-2 and survivin. Importantly, studies of patient samples indicate that expression of PDK4 and phosphorylation of Smad2, an indicator of TGFβ pathway activation, show a strong correlation and that both positively associate with chemoresistance in colorectal cancer. These findings indicate that the TGFβ/PDK4 signaling axis plays an important role in the response of colorectal cancer to chemotherapy. A major implication of our studies is that inhibition of PDK4 may have considerable therapeutic potential to overcome drug resistance in colorectal cancer patients, which warrants the development of PDK4-specific inhibitors.

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Heightened condition dependent expression of structural colouration in the faces, but not wings, of male and female flies

Current Zoology ◽

10.1093/cz/zoab087 ◽

2021 ◽

Author(s):

Thomas E White ◽

Amy Locke ◽

Tanya Latty

Keyword(s):

Mate Choice ◽

Condition Dependence ◽

Sexually Dimorphic ◽

Male And Female ◽

Honest Signals ◽

Mutual Mate Choice ◽

Close Range ◽

Males And Females ◽

Structural Colouration

Abstract Structurally coloured sexual signals are a conspicuous and widespread class of ornament used in mate choice, though the extent to which they encode information on the quality of their bearers is not fully resolved. Theory predicts that signalling traits under strong sexual selection as honest indicators should evolve to be more developmentally integrated and exaggerated than nonsexual traits, thereby leading to heightened condition dependence. Here we test this prediction through examination of the sexually dimorphic faces and wings of the cursorial fly Lispe cana. Males and females possess structural UV-white and golden faces, respectively, and males present their faces and wings to females during close-range, ground-based courtship displays, thereby creating the opportunity for mutual inspection. Across a field-collected sample of individuals, we found that the appearance of the faces of both sexes scaled positively with individual condition, though along separate axes. Males in better condition expressed brighter faces as modelled according to conspecific flies, whereas condition scaled with facial saturation in females. We found no such relationships for their wing interference pattern nor abdomens, with the latter included as a nonsexual control. Our results suggest that the structurally coloured faces, but not the iridescent wings, of male and female Lispe cana are reliable guides to individual quality and support the broader potential for structural colours as honest signals. They also highlight the potential for mutual mate choice in this system, while arguing for one of several alternate signalling roles for wing interferences patterns among the myriad taxa which bear them.

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Sex identification in embryos and adults of Darwin’s finches

PLoS ONE ◽

10.1371/journal.pone.0237687 ◽

2021 ◽

Vol 16 (3) ◽

pp. e0237687

Author(s):

Mariya P. Dobreva ◽

Joshua G. Lynton-Jenkins ◽

Jaime A. Chaves ◽

Masayoshi Tokita ◽

Camille Bonneaud ◽

...

Keyword(s):

Field Studies ◽

Sexually Dimorphic ◽

Genetic Studies ◽

Darwin's Finches ◽

Darwin’S Finches ◽

Specific Morphology ◽

Males And Females ◽

Primer Sets ◽

Dimorphic Species ◽

Source Of Error

Darwin’s finches are an iconic example of adaptive radiation and evolution under natural selection. Comparative genetic studies using embryos of Darwin’s finches have shed light on the possible evolutionary processes underlying the speciation of this clade. Molecular identification of the sex of embryonic samples is important for such studies, where this information often cannot be inferred otherwise. We tested a fast and simple chicken embryo protocol to extract DNA from Darwin’s finch embryos. In addition, we applied minor modifications to two of the previously reported PCR primer sets for CHD1, a gene used for sexing adult passerine birds. The sex of all 29 tested embryos of six species of Darwin’s finches was determined successfully by PCR, using both primer sets. Next to embryos, hatchlings and fledglings are also impossible to distinguish visually. This extends to juveniles of sexually dimorphic species which are yet to moult in adult-like plumage and beak colouration. Furthermore, four species of Darwin’s finches are monomorphic, males and females looking alike. Therefore, sex assessment in the field can be a source of error, especially with respect to juveniles and mature monomorphic birds outside of the mating season. We caught 567 juveniles and adults belonging to six species of Darwin’s finches and only 44% had unambiguous sex-specific morphology. We sexed 363 birds by PCR: individuals sexed based on marginal sex specific morphological traits; and birds which were impossible to classify in the field. PCR revealed that for birds with marginal sex specific traits, sexing in the field produced a 13% error rate. This demonstrates that PCR based sexing can improve field studies on Darwin’s finches, especially when individuals with unclear sex-related morphology are involved. The protocols used here provide an easy and reliable way to sex Darwin’s finches throughout ontogeny, from embryos to adults.

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A Novel Therapeutic Target, BACH1, Regulates Cancer Metabolism

10.20944/preprints202101.0626.v1 ◽

2021 ◽

Author(s):

Jiyoung Lee ◽

Joselyn Padilla

Keyword(s):

Cancer Cells ◽

Cancer Patients ◽

Transcriptional Activation ◽

Pyruvate Dehydrogenase ◽

Therapeutic Target ◽

Metabolic Pathways ◽

Cancer Metabolism ◽

Aerobic Glycolysis ◽

Pyruvate Dehydrogenase Kinase ◽

Migration And Invasion

BTB domain and CNC homology 1 (BACH1) is a highly expressed transcription factor in tumors including breast and lung, relative to their non-tumor tissues. BACH1 is known to regulate multiple physiological processes including heme homeostasis, oxidative stress response, senescence, cell cycle, and mitosis. In a tumor, BACH1 promotes invasion and metastasis of cancer cells, and the expression of BACH1 presents a poor outcome for cancer patients including breast cancer patients. Recent studies identified novel functional roles of BACH1 in the regulation of metabolic pathways in cancer cells. BACH1 inhibits mitochondrial metabolism through transcriptional suppression of mitochondrial membrane genes. In addition, BACH1 suppresses activity of pyruvate dehydrogenase (PDH), a key enzyme that converts pyruvate to acetyl-CoA for the citric acid (TCA) cycle through transcriptional activation of pyruvate dehydrogenase kinase (PDK). Moreover, BACH1 increases glucose uptake and lactate secretion in aerobic glycolysis through the expression of metabolic enzymes involved such as hexokinase 2 (HK2) and glyceraldehyde 3- phosphate dehydrogenase (GAPDH). Pharmacological or genetic inhibition of BACH1 could reprogramme metabolic pathways, subsequently rendering metabolic vulnerability of cancer cells. Furthermore, inhibition of BACH1 decreased antioxidant-induced glycolysis rates as well as reduced migration and invasion of cancer cells, suggesting BACH1 as a potentially useful cancer therapeutic target.

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Sex Differences in Exercise-Induced Bronchoconstriction in Athletes: A Systematic Review and Meta-Analysis

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph17197270 ◽

2020 ◽

Vol 17 (19) ◽

pp. 7270

Author(s):

Daniel Enrique Rodriguez Bauza ◽

Patricia Silveyra

Keyword(s):

Sex Differences ◽

Female Athletes ◽

Meta Analysis ◽

Sexually Dimorphic ◽

Atopic Status ◽

Management Plans ◽

Disease Experience ◽

Males And Females ◽

Male Sex ◽

Exercise Induced

Exercise-induced bronchoconstriction (EIB) is a common complication of athletes and individuals who exercise regularly. It is estimated that about 90% of patients with underlying asthma (a sexually dimorphic disease) experience EIB; however, sex differences in EIB have not been studied extensively. With the goal of better understanding the prevalence of EIB in males and females, and because atopy has been reported to occur at higher rates in athletes, in this study, we investigated sex differences in EIB and atopy in athletes. A systematic literature review identified 60 studies evaluating EIB and/or atopy in post-pubertal adult athletes (n = 7501). Collectively, these studies reported: (1) a 23% prevalence of EIB in athletes; (2) a higher prevalence of atopy in male vs. female athletes; (3) a higher prevalence of atopy in athletes with EIB; (4) a significantly higher rate of atopic EIB in male vs. female athletes. Our analysis indicates that the physiological changes that occur during exercise may differentially affect male and female athletes, and suggest an interaction between male sex, exercise, and atopic status in the course of EIB. Understanding these sex differences is important to provide personalized management plans to athletes with underlying asthma and/or atopy.

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Effect of redox imbalance on protein modifications in lymphocytes of psoriatic patients

The Journal of Biochemistry ◽

10.1093/jb/mvz096 ◽

2019 ◽

Vol 167 (3) ◽

pp. 323-331 ◽

Cited By ~ 5

Author(s):

Piotr Wójcik ◽

Agnieszka Gęgotek ◽

Adam Wroński ◽

Anna Jastrząb ◽

Agnieszka Żebrowska ◽

...

Keyword(s):

Metabolic Pathways ◽

Caspase 3 ◽

Psoriasis Vulgaris ◽

Redox Status ◽

Redox Activity ◽

Apoptotic Pathway ◽

Protein Modifications ◽

Redox Imbalance ◽

Pathway Activation ◽

Enhanced Expression

Abstract Lymphocytes are one of the most important cells involved in the pathophysiology of psoriasis; therefore, the aim of this study was to assess the redox imbalance and protein modifications in the lymphocytes of patients with psoriasis vulgaris (PsV) or psoriatic arthritis (PsA). The results show a stronger shift in redox status to pro-oxidative conditions (observed as an increased reactive oxygen species level, a decrease in catalase activity and lower levels of glutathione peroxidase and vitamin E compared with healthy controls) in the lymphocytes of PsA than PsV patients. It is also favoured by the enhanced level of activators of the Nrf2 transcription factor in lymphocytes of PsV compared with decreased of these proteins level in PsA. Moreover, the differential modifications of proteins by lipid peroxidation products 4-oxononenal (mainly binding proteins) and malondialdehyde (mainly catalytic proteins with redox activity), promoted a pro-apoptotic pathway in lymphocytes of PsV, which was manifested by enhanced expression of pro-apoptotic caspases, particularly caspase 3. Taken together, differences in Nrf2 pathway activation may be responsible for the differential level of redox imbalance in lymphocytes of patients with PsV and PsA. This finding may enable identification of a targeted therapy to modify the metabolic pathways disturbed in psoriasis.

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Variation in Chin and Mandibular Symphysis Size and Shape in Males and Females: A CT-Based Study

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph17124249 ◽

2020 ◽

Vol 17 (12) ◽

pp. 4249

Author(s):

Tatiana Sella Tunis ◽

Israel Hershkovitz ◽

Hila May ◽

Alexander Dan Vardimon ◽

Rachel Sarig ◽

...

Keyword(s):

Sexual Selection ◽

Anatomical Landmark ◽

Anatomical Structure ◽

Sexually Dimorphic ◽

Selection Theory ◽

Size And Shape ◽

Size Index ◽

Sexual Selection Theory ◽

Males And Females ◽

Anthropological Literature

The chin is a unique anatomical landmark of modern humans. Its size and shape play an important role from the esthetic perspective. However, disagreement exists in the dental and anthropological literature regarding the sex differences in chin and symphysis morphometrics. The “sexual selection” theory is presented as a possible reason for chin formation in our species; however, many other contradictory theories also exist. This study’s aims were therefore to determine how chin and symphysis size and shape vary with sex, and to discuss “sexual selection” theory as a reason for its formation. Head and neck computed tomography (CT) scans of 419 adults were utilized to measure chin and symphysis sizes and shapes. The chin and symphysis measures were compared between the sexes using an independent-samples t-test, a Mann–Whitney test, and the F-statistic. The chin width was significantly greater in males than in females (p < 0.001), whereas the chin height, area, and size index were significantly greater in females (p < 0.001). Symphysis measures did not differ significantly between the sexes. Size accounted for 2–14% of the chin variance and between 24–33% of the symphysis variance. Overall, the chin was found to be a more heterogeneous anatomical structure than the symphysis, as well as more sexually dimorphic.

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