Dataset Information

Development of Novel IP6K Inhibitors for the Treatment of Obesity and Obesity-Induced Metabolic Dysfunctions.

ABSTRACT: Obesity and obesity-induced metabolic dysfunctions are significant risk factors for nonalcoholic fatty liver disease and cardiovascular diseases. Thus, obesity is an economic and social burden in developed countries. Blocking the synthesis of inositol pyrophosphates by inositol hexakisphosphate kinase (IP6K) has been identified as a potential therapeutic strategy for obesity and related diseases. We have developed a novel and potent IP6K inhibitor 20 (UNC7467) (IC₅₀ values: IP6K1 8.9 nM; IP6K2 4.9 nM; IP6K3 1320 nM). Inositol phosphate profiling of the HCT116 colon cancer cell line demonstrates that 20 reduced levels of inositol pyrophosphates by 66-81%, without significantly perturbing levels of other inositol phosphates. Furthermore, intraperitoneal injection of 20 in diet-induced obese mice improved glycemic profiles, ameliorated hepatic steatosis, and reduced weight gain without altering food intake. Thus, inhibitor 20 can be used as an in vivo probe for IP6K-related research. Moreover, it may have therapeutic relevance in treating obesity and related diseases.

SUBMITTER: Zhou Y

PROVIDER: S-EPMC9383042 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Development of Novel IP6K Inhibitors for the Treatment of Obesity and Obesity-Induced Metabolic Dysfunctions.

Zhou Yubai Y Mukherjee Sandip S Huang Daowei D Chakraborty Molee M Gu Chunfang C Zong Guangning G Stashko Michael A MA Pearce Kenneth H KH Shears Stephen B SB Chakraborty Anutosh A Wang Huanchen H Wang Xiaodong X

Journal of medicinal chemistry 20220425 9

Obesity and obesity-induced metabolic dysfunctions are significant risk factors for nonalcoholic fatty liver disease and cardiovascular diseases. Thus, obesity is an economic and social burden in developed countries. Blocking the synthesis of inositol pyrophosphates by inositol hexakisphosphate kinase (IP6K) has been identified as a potential therapeutic strategy for obesity and related diseases. We have developed a novel and potent IP6K inhibitor <b>20</b> (UNC7467) (IC<sub>50</sub> values: IP6 ...[more]

PMID: 35467861

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Project description:BackgroundObesity is associated with insulin resistance (IR) and metabolic dysfunction-associated steatotic liver disease (MASLD). Genistein, an isoflavone, is a promising natural compound for preventing and treating obesity and metabolic dysfunctions. We aimed to investigate the sex-specific protective effects of genistein on obesity, IR, and MASLD in a murine model of sex hormone deprivation with diet-induced obesity (DIO), mimicking postmenopausal women or aging men with metabolic syndrome.MethodsGonadectomized and sham-operated C57BL/6NJcl mice were fed a high-fat high-sucrose diet for 4 weeks to induce obesity (7 mice per group). In gonadectomized mice, genistein (16 mg/kg/day) or vehicle (7.5% dimethyl sulfoxide) was orally administered for 45 days. We assessed glucose homeostasis parameters, hepatic histopathology, and hepatic gene expression to investigate the effects of gonadectomy and genistein treatment.ResultsGonadectomy exacerbated adiposity in both sexes. Ovariectomy diminished the protective effects of female gonadal hormones on the homeostatic model assessment for insulin resistance (HOMA-IR), serum alanine transaminase levels, hepatic steatosis score, and the expression of hepatic genes associated with MASLD progression and IR, such as Fasn, Srebf1, Saa1, Cd36, Col1a1, Pck1, and Ppargc1a. Genistein treatment in gonadectomized mice significantly reduced body weight gain and the hepatic steatosis score in both sexes. However, genistein treatment significantly attenuated HOMA-IR and the expression of the hepatic genes only in female mice.ConclusionGenistein treatment mitigates DIO-related MASLD in both male and female gonadectomized mice. Regarding hepatic gene expression associated with MASLD and IR, the beneficial effect of genistein was significantly evident only in female mice. This study suggests a potential alternative application of genistein in individuals with obesity and sex hormone deprivation, yet pending clinical trials.

Project description:AimsThe association of strictly defined metabolic healthy obese (MHO) with subclinical cardiac function was unclear. Our study aims to examine the role of MHO in subclinical cardiac dysfunction in a Chinese population.Methods and resultsThe study subjects were recruited from Danyang from 2017 to 2019. Obesity was defined by body mass index (BMI) categories (normal weight, overweight and obesity). Metabolic health was strictly defined as having neither any of the guidelines recommended metabolic syndrome components nor insulin resistance. Thus, subjects were grouped by BMI categories and metabolic health status as six groups. Preclinical systolic (global longitudinal strain [GLS]) and diastolic function were assessed by 2D speckle tracking, and transmitral and tissue Doppler imaging, respectively. The 2757 participants (mean age ± standard deviation, 52.7 ± 11.7 years) included 1613 (58.5%) women, 999 (36.2%) obese, 2080 (75.4%) metabolically unhealthy and 93 (3.4%) MHO participants. After adjustment for covariates, the trend was similar for left ventricular (LV) ejection fraction (Ptrend ≥ 0.07) but significantly worse for GLS, e' and E/e' (Ptrend ≤ 0.02) across the six groups or passing from normal weight to obese individuals irrespective of metabolic status. MHO participants had lower GLS (20.4 vs. 21.4%) and e' (9.6 vs. 10.6 cm/s) compared with controls (P < 0.0001) but had similar GLS (P = 0.47) compared with metabolically unhealthy obese (MUO). Regardless of obesity status, metabolically unhealthy participants had worse diastolic function compared with their metabolically healthy counterparts (P ≤ 0.0004). Compared with controls, MHO individuals were at higher risk of subclinical LV systolic dysfunction (OR = 3.44, 95% CI = 1.25-9.49, P = 0.02). These results were robust to sensitivity analysis.ConclusionsMHO was substantially associated with worse subclinical systolic function although early diastolic dysfunction seemed to be more accentuated in MUO.

Dataset Information

Development of Novel IP6K Inhibitors for the Treatment of Obesity and Obesity-Induced Metabolic Dysfunctions.

Publications

Development of Novel IP6K Inhibitors for the Treatment of Obesity and Obesity-Induced Metabolic Dysfunctions.

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