Polycystic ovary syndrome (PCOS) is a complex syndrome involving both endocrine and metabolic disorders. Gut microbiota and the intestinal immune factor IL-22 play an important role in the pathogenesis of PCOS. However, the therapeutic role of IL-22 in high androgen-induced PCOS mice is not clear. We aimed to determine the therapeutic effects of IL-22 on the DHEA-induced PCOS mouse model and to explore the possible mechanism of IL-22 in regulating hyperandrogenism-associated PCOS. Insulin resistance levels and ovarian functions were investigated in DHEA-induced PCOS mice with or without additional IL-22 treatment. We found that IL-22 could reverse insulin resistance, disturbed estrous cycle, abnormal ovary morphology, and decreased embryo number in DHEA mice. Mechanistically, IL-22 upregulated the browning of white adipose tissue in DHEA mice. This study demonstrated that IL-22-associated browning of white adipose tissue regulated insulin sensitivity and ovarian functions in PCOS, suggesting that IL-22 may be of value for the treatment of PCOS with a hyperandrogenism phenotype.
Xinyu Qi, Chuyu Yun, Baoying Liao, Jie Qiao, and Yanli Pang
Sian J S Simpson, Lorna I F Smith, Peter M Jones, and James E Bowe
The corticotropin-releasing hormone (CRH) family of peptides, including urocortin (UCN) 1, 2 and 3, are established hypothalamic neuroendocrine peptides, regulating the physiological and behaviour responses to stress indirectly, via the hypothalamic-pituitary-adrenal (HPA) axis. More recently, these peptides have been implicated in diverse roles in peripheral organs through direct signalling, including in placental and pancreatic islet physiology. CRH has been shown to stimulate insulin release through activation of its cognate receptors, CRH receptor 1 (CRHR1) and 2. However, the physiological significance of this is unknown. We have previously reported that during mouse pregnancy, expression of CRH peptides increase in mouse placenta suggesting that these peptides may play a role in various biological functions associated with pregnancy, particularly the pancreatic islet adaptations that occur in the pregnant state to compensate for the physiological increase in maternal insulin resistance. In the current study, we show that mouse pregnancy is associated with increased circulating levels of UCN2 and that when we pharmacologically block endogenous CRHR signalling in pregnant mice, impairment of glucose tolerance is observed. This effect on glucose tolerance was comparable to that displayed with specific CRHR2 blockade and not with specific CRHR1 blockade. No effects on insulin sensitivity or the proliferative capacity of β-cells were detected. Thus, CRHR2 signalling appears to be involved in β-cell adaptive responses to pregnancy in the mouse, with endogenous placental UCN2 being the likely signal mediating this.
Sarah L Craig, Victor A Gault, Gerd Hamscher, and Nigel Irwin
Recent studies have characterised the biological properties and glucose-dependent insulinotropic polypeptide (GIP) potentiating actions of an enzymatically stable, C-terminal hexapeptide fragment of the gut hormone xenin, namely Ψ-xenin-6. Given the primary therapeutic target of clinically approved dipeptidyl peptidase-4 (DPP-4) inhibitor drugs is augmentation of the incretin effect, the present study has assessed the capacity of Ψ-xenin-6 to enhance the antidiabetic efficacy of sitagliptin in high fat fed (HFF) mice. Individual administration of either sitagliptin or Ψ-xenin-6 alone for 18 days resulted in numerous metabolic benefits and positive effects on pancreatic islet architecture. As expected, sitagliptin therapy was associated with elevated circulating GIP and GLP-1 levels, with concurrent Ψ-xenin-6 not elevating these hormones or enhancing DPP-4 inhibitory activity of the drug. However, combined sitagliptin and Ψ-xenin-6 therapy in HFF mice was associated with further notable benefits, beyond that observed with either treatment alone. This included body weight change similar to lean controls, more pronounced and rapid benefits on circulating glucose and insulin as well as additional improvements in attenuating gluconeogenesis. Favourable effects on pancreatic islet architecture and peripheral insulin sensitivity were more apparent with combined therapy. Expression of hepatic genes involved in gluconeogenesis and insulin action were partially, or fully, restored to normal levels by the treatment regimens, with beneficial effects more prominent in the combination treatment group. These data demonstrate that combined treatment with Ψ-xenin-6 and sitagliptin did not alter glucose tolerance but does offer some metabolic advantages, which merit further consideration as a therapeutic option for type 2 diabetes.
Yoshinori Kanemaru, Norio Harada, Satoko Shimazu-Kuwahara, Shunsuke Yamane, Eri Ikeguchi, Yuki Murata, Sakura Kiyobayashi, Tomonobu Hatoko, and Nobuya Inagaki
Glucose-dependent insulinotropic polypeptide (GIP) is an incretin secreted from enteroendocine K cells after nutrient ingestion. Fat strongly induces GIP secretion, and GIP hypersecretion is involved in high-fat diet-induced obesity and insulin resistance. Aging also induces GIP hypersecretion, but its effect on body weight gain and insulin sensitivity remains unclear. In the present study, we investigated the effect of GIP on age-related body weight gain and insulin resistance using GIP-knockout homozygous (GIP−/ −) and heterozygous (GIP+/ −) mice, which have entirely absent and 50% reduced GIP secretion compared to wild-type (WT) mice, respectively. Under 12% fat-containing normal diet feeding condition, body weight was significantly lower in GIP−/ − mice compared to that in WT and GIP+/ − mice from 38 weeks of age, while there was no significant difference between WT and GIP+/ − mice. Visceral and s.c. fat mass were also significantly lower in GIP−/ − mice compared to those in WT and GIP+/ − mice. During oral glucose tolerance test, blood glucose levels did not differ among the three groups. Insulin levels were significantly lower in GIP−/ − mice than those in WT and GIP+/ − mice. During insulin tolerance test, GIP−/ − mice showed higher insulin sensitivity than that of WT and GIP+/ − mice. Adiponectin mRNA levels were increased and leptin mRNA levels tended to be decreased in adipose tissue of GIP−/ − mice. These results demonstrate that GIP is involved in age-related obesity and insulin resistance and that inhibition of GIP secretion alleviates age-related fat mass gain and insulin resistance under carbohydrate-based diet feeding condition.
Zhe-Zhen Liao, Xiao-Yan Qi, Ya-Di Wang, Jiao-Yang Li, Qian-Qian Gu, Can Hu, Yin Hu, Heng Sun, Li Ran, Jing Yang, Jiang-Hua Liu, and Xin-Hua Xiao
Remodeling of energy-storing white fat into energy-consuming beige fat has led to a promising new approach to alleviate adiposity. Several studies have shown adipokines can induce white adipose tissue (WAT) beiging through autocrine or paracrine actions. Betatrophin, a novel adipokine, has been linked to energy expenditure and lipolysis but not clearly clarified. Here, we using high-fat diet-induced obesity to determine how betatrophin modulate beiging and adiposity. We found that betatrophin-knockdown mice displayed less white fat mass and decreased plasma TG and NEFA levels. Consistently, inhibition of betatrophin leads to the phenotype change of adipocytes characterized by increased mitochondria contents, beige adipocytes and mitochondria biogenesis-specific markers both in vivo and in vitro. Of note, blocking AMP-activated protein kinase (AMPK) signaling pathway is able to abolish enhanced beige-like characteristics in betatrophin-knockdown adipocytes. Collectively, downregulation of betatrophin induces beiging in white adipocytes through activation of AMPK signaling pathway. These processes suggest betatrophin as a latent therapeutic target for obesity.
Zhengxiang Huang, Lili Huang, Chengjian Wang, Shanli Zhu, Xinzhou Qi, Yang Chen, Yanjun Zhang, Michael A Cowley, Johannes D Veldhuis, and Chen Chen
The well-documented hormonal disturbance in a general obese population is characterised by an increase in insulin secretion and a decrease in growth hormone (GH) secretion. Such hormonal disturbance promotes an increase in fat mass, which deteriorates obesity and accelerates the development of insulin resistance and type 2 diabetes. While the pathological consequence is alarming, the pharmaceutical approach attempting to correct such hormonal disturbance remains limited. By applying an emerging anti-diabetic drug, the sodium-glucose cotransporter 2 inhibitor, dapagliflozin (1 mg/kg/day for 10 weeks), to a hyperphagic obese mouse model, we observed a significant improvement in insulin and GH secretion as early as 4 weeks after the initiation of the treatment. Restoration of pathological disturbance of insulin and GH secretion reduced fat accumulation and preserved lean body mass in the obese animal model. Such phenotypic improvement followed with concurrent improvements in glucose and lipid metabolism, insulin sensitivity, as well as the expression of metabolic genes that were regulated by insulin and GH. In conclusion, 10 weeks of treatment with dapagliflozin effectively reduces hyperinsulinemia and restores pulsatile GH secretion in the hyperphagic obese mice with considerable improvement in lipid and glucose metabolism. Promising outcomes from this study may provide insights into drug intervention to correct hormonal disturbance in obesity to delay the diabetes progression.
Zeravan A Mohammed, Robert S Robinson, Rachel Harris, Yasmin McLaughlin, Kaitlin E M Turnbull, George E Mann, and Kathryn J Woad
Reproductive tract inflammatory disease (RTID) commonly occurs after the traumatic events of parturition and adversely affects follicular function. This study is the first to describe the cellular and steroidogenic characteristics of corpora lutea from cattle with RTID and the effects of pathogen-associated molecular patterns (PAMPs) on luteal angiogenesis and function in vitro. Luteal weight (P < 0.05) and progesterone content (P < 0.05) were reduced (1.2-fold) in cows with RTID, accompanied by reduced CYP11A (P < 0.05), HSD3B (P < 0.01) and STAR (P < 0.01) protein expression. Immunohistochemistry revealed that luteal vascularity (VWF) and pericyte (ACTA2) coverage were >3-fold lower in RTID cows (P < 0.05). To link these observations to bacterial infection and determine specificity of action, a physiologically relevant luteal angiogenesis culture system examined the effects of PAMPs on endothelial cell (EC) network formation and progesterone production, in the presence of pro-angiogenic factors. Luteal EC networks were reduced ≤95% (P < 0.05) by lipopolysaccharide (LPS, toll-like receptor (TLR) 4 agonist) but not by TLR2 agonists lipoteichoic acid or peptidoglycan. Conversely, progesterone production and steroidogenic protein expression were unaffected by PAMPs (P > 0.05). Moreover, the adverse effect of LPS on luteal EC networks was dose-dependent and effective from 1 ng/mL (P < 0.05), while few EC networks were present above 10 ng/mL LPS (P < 0.001). LPS reduced proliferation (P < 0.05) and increased apoptosis of EC (P < 0.001). The specific TLR4 inhibitor TAK242 reversed the effects of LPS on EC networks. In conclusion, luteal vasculature is adversely sensitive to LPS acting via TLR4, therefore ovarian exposure to LPS from any Gram-negative bacterial infection will profoundly influence subsequent reproductive potential.
Terese M Zidon, Jaume Padilla, Kevin L Fritsche, Rebecca J Welly, Leighton T McCabe, Olivia E Stricklin, Aaron Frank, Youngmin Park, Deborah J Clegg, Dennis B Lubahn, Jill A Kanaley, and Victoria J Vieira-Potter
Loss of ovarian hormones leads to increased adiposity and insulin resistance (IR), increasing the risk for cardiovascular and metabolic diseases. The purpose of this study was to investigate whether the molecular mechanism behind the adverse systemic and adipose tissue-specific metabolic effects of ovariectomy requires loss of signaling through estrogen receptor alpha (ERα) or estrogen receptor β (ERβ). We examined ovariectomized (OVX) and ovary-intactwild-type (WT), ERα-null (αKO), and ERβ-null (βKO) female mice (age ~49 weeks; n = 7–12/group). All mice were fed a phytoestrogen-free diet (<15 mg/kg) and either remained ovary-intact (INT) or were OVX and followed for 12 weeks. Body composition, energy expenditure, glucose tolerance, and adipose tissue gene and protein expression were analyzed. INT αKO were ~25% fatter with reduced energy expenditure compared to age-matched INT WT controls and βKO mice (all P < 0.001). Following OVX, αKO mice did not increase adiposity or experience a further increase in IR, unlike WT and βKO, suggesting that loss of signaling through ERα mediates OVX-induced metabolic dysfunction. In fact, OVX in αKO mice (i.e., signaling through ERβ in the absence of ERα) resulted in reduced adiposity, adipocyte size, and IR (P < 0.05 for all). βKO mice responded adversely to OVX in terms of increased adiposity and development of IR. Together, these findings challenge the paradigm that ERα mediates metabolic protection over ERβ in all settings. These findings lead us to suggest that, following ovarian hormone loss, ERβ may mediate protective metabolic benefits.
Shisan Xu, Fangjing Xie, Li Tian, Samane Fallah, Fatemeh Babaei, Sinai H C Manno, Francis A M Manno III, Lina Zhu, Kin Fung Wong, Yimin Liang, Rajkumar Ramalingam, Lei Sun, Xin Wang, Robert Plumb, Lee Gethings, Yun Wah Lam, and Shuk Han Cheng
Sexual differences have been observed in the onset and prognosis of human cardiovascular diseases, but the underlying mechanisms are not clear. Here, we found that zebrafish heart regeneration is faster in females, can be accelerated by estrogen and is suppressed by the estrogen-antagonist tamoxifen. Injuries to the zebrafish heart, but not other tissues, increased plasma estrogen levels and the expression of estrogen receptors, especially esr2a. The resulting endocrine disruption induces the expression of the female-specific protein vitellogenin in male zebrafish. Transcriptomic analyses suggested heart injuries triggered pronounced immune and inflammatory responses in females. These responses, previously shown to elicit heart regeneration, could be enhanced by estrogen treatment in males and reduced by tamoxifen in females. Furthermore, a prior exposure to estrogen preconditioned the zebrafish heart for an accelerated regeneration. Altogether, this study reveals that heart regeneration is modulated by an estrogen-inducible inflammatory response to cardiac injury. These findings elucidate a previously unknown layer of control in zebrafish heart regeneration and provide a new model system for the study of sexual differences in human cardiac repair.
Hui Yu, Zoe Thompson, Sylee Kiran, Graham L Jones, Lakshmi Mundada, Surbhi, Marcelo Rubinstein, and Malcolm J Low
Proopiomelanocortin (POMC) neurons in the hypothalamic arcuate nucleus (ARC) are essential for normal energy homeostasis. Maximal ARC Pomc transcription is dependent on neuronal Pomc enhancer 1 (nPE1), located 12 kb upstream from the promoter. Selective deletion of nPE1 in mice decreases ARC Pomc expression by 70%, sufficient to induce mild obesity. Because nPE1 is located exclusively in the genomes of placental mammals, we questioned whether its hypomorphic mutation would also alter placental Pomc expression and the metabolic adaptations associated with pregnancy and lactation. We assessed placental development, pup growth, circulating leptin and expression of Pomc, Agrp and alternatively spliced leptin receptor (LepR) isoforms in the ARC and placenta of Pomc∆1/∆1 and Pomc+/+ dams. Despite indistinguishable body weights, lean mass, food intake, placental histology and Pomc expression and overall pregnancy outcomes between the genotypes, Pomc ∆1/∆1 females had increased pre-pregnancy fat mass that paradoxically decreased to control levels by parturition. However, Pomc∆1/∆1 dams had exaggerated increases in circulating leptin, up to twice of that of the typically elevated levels in Pomc+/+ mice at the end of pregnancy, despite their equivalent fat mass. Pomc∆1/∆1dams also had increased placental expression of soluble leptin receptor (LepRe), although the protein levels of LEPRE in circulation were the same as Pomc+/+ controls. Together, these data suggest that the hypomorphic Pomc∆1/∆1 allele is responsible for the perinatal super hyperleptinemia of Pomc∆1/∆1 dams, possibly due to upregulated leptin secretion from individual adipocytes.