Associations of Lifestyle and Genetic Risks with Obesity and Related Chronic Diseases in the UK Biobank: A Prospective Cohort Study.

BACKGROUND: Interplay between lifestyle risk scores (LRSs) and genetic risk scores (GRSs) on obesity and related chronic diseases are underinvestigated and necessary for understanding obesity causes and developing prevention strategies. OBJECTIVES: This study aimed to investigate independent and joint associations and interactions of LRS and GRS with obesity prevalence and risks of diabetes, cardiovascular disease (CVD), and obesity-related cancer. METHODS: In this cohort study of 444,957 UK Biobank participants [age: 56.5 ± 8.1 y; BMI (in kg/m2): 27.4 ± 4.7], LRS included physical activity, dietary score, sedentary behavior, sleep duration, and smoking (range: 0-20, each factor had 5 levels). GRS was calculated based on 941 genetic variants related to BMI. Both scores were categorized into quintiles. Obesity (n = 106,301) was defined as baseline BMI ≥30. Incident diabetes (n = 16,311), CVD (n = 18,076), and obesity-related cancer (n = 17,325) were ascertained through linkage to registries over a median of 12-y follow-up. RESULTS: The LRS and GRS were independently positively associated with all outcomes. Additive interactions of LRS and GRS were observed for all outcomes (P < 0.021). Comparing the top with bottom LRS quintile, prevalence differences (95% CIs) for obesity were 17.8% (15.9%, 19.7%) in the top GRS quintile and 10.7% (8.3%, 13.1%) in the bottom GRS quintile; for diabetes, CVD, and obesity-related cancer, incidence rate differences associated with per SD increase in LRS were greater in the top than that in the bottom GRS quintile. Participants from top quintiles of both LRS and GRS had 6.16-fold, 3.81-fold, 1.56-fold, and 1.44-fold higher odds/risks of obesity, diabetes, CVD, and obesity-related cancer, respectively, than those from bottom quintiles of both scores. CONCLUSIONS: Higher LRS was associated with higher obesity prevalence and risks of related chronic diseases regardless of GRS, highlighting the broad benefits of healthy lifestyles. Additive gene-lifestyle interactions emphasize the public health importance of lifestyle interventions among people with high genetic risks.

Pharmacological Characterization of SDX-7320/Evexomostat: A Novel Methionine Aminopeptidase Type 2 Inhibitor with Anti-tumor and Anti-metastatic Activity.

Methionine aminopeptidase type 2 (METAP2) is a ubiquitous, evolutionarily conserved metalloprotease fundamental to protein biosynthesis which catalyzes removal of the N-terminal methionine residue from nascent polypeptides. METAP2 is an attractive target for cancer therapeutics based upon its over-expression in multiple human cancers, the importance of METAP2-specific substrates whose biological activity may be altered following METAP2 inhibition, and additionally, that METAP2 was identified as the target for the anti-angiogenic natural product, fumagillin. Irreversible inhibition of METAP2 using fumagillin analogues has established the anti-angiogenic and anti-tumor characteristics of these derivatives; however, their full clinical potential has not been realized due to a combination of poor drug-like properties and dose-limiting central nervous system (CNS) toxicity. This report describes the physicochemical and pharmacological characterization of SDX-7320 (evexomostat), a polymer-drug conjugate of the novel METAP2 inhibitor (METAP2i) SDX-7539. In vitro binding, enzyme, and cell-based assays demonstrated that SDX-7539 is a potent and selective METAP2 inhibitor. In utilizing a high molecular weight, water-soluble polymer to conjugate the novel fumagillol-derived, cathepsin-released, METAP2i SDX-7539, limitations observed with prior generation, small molecule fumagillol derivatives were ameliorated including reduced CNS exposure of the METAP2i, and prolonged half-life enabling convenient administration. Multiple xenograft and syngeneic cancer models were utilized to demonstrate the anti-tumor and anti-metastatic profile of SDX-7320. Unlike polymer-drug conjugates in general, reductions in small molecule-equivalent efficacious doses following polymer conjugation were observed. SDX-7320 has completed a phase I clinical safety study in patients with late-stage cancer and is currently being evaluated in multiple phase Ib/II clinical studies in patients with advanced solid tumors.

A randomized, double-blind, placebo-controlled phase 2 study to assess safety, tolerability, and efficacy of RT001 in patients with amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: RT001 is a deuterated synthetic homologue of linoleic acid, which makes membrane polyunsaturated fatty acids resistant to lipid peroxidation, a process involved in motor neuron degeneration in amyotrophic lateral sclerosis (ALS). METHODS: We conducted a randomized, multicenter, placebo-controlled clinical trial. Patients with ALS were randomly allocated to receive either RT001 or placebo for 24 weeks. After the double-blind period, all patients received RT001 during an open-label phase for 24 weeks. The primary outcome measures were safety and tolerability. Key efficacy outcomes included the ALS Functional Rating Scale (ALSFRS-R), percent predicted slow vital capacity, and plasma neurofilament light chain concentration. RESULTS: In total, 43 patients (RT001 = 21; placebo = 22) were randomized. RT001 was well tolerated; one patient required dose reduction due to adverse events (AEs). Numerically, there were more AEs in the RT001 group compared to the placebo group (71% versus 55%, p = 0.35), with gastrointestinal symptoms being the most common (43% in RT001, 27% in placebo, p = 0.35). Two patients in the RT001 group experienced a serious AE, though unrelated to treatment. The least-squares mean difference in ALSFRS-R total score at week 24 of treatment was 1.90 (95% confidence interval = -1.39 to 5.19) in favor of RT001 (p = 0.25). The directions of other efficacy outcomes favored RT001 compared to placebo, although no inferential statistics were performed. CONCLUSIONS: Initial data indicate that RT001 is safe and well tolerated. Given the exploratory nature of the study, a larger clinical trial is required to evaluate its efficacy.

Healthy Lifestyle Index and Risk of Cardiovascular Disease Among Postmenopausal Women With Normal Body Mass Index.

Background A lifestyle comprising a healthy diet, light alcohol consumption, no smoking, and moderate or intense physical activity has been associated with reduced risk of cardiovascular disease (CVD). We examined the association of a healthy lifestyle index (HLI), derived from scores for each of these components plus waist circumference, with the risk of incident CVD and CVD subtypes in postmenopausal women with normal body mass index (18.5-<25.0 kg/m2). Methods and Results We studied 40 118 participants in the Women's Health Initiative, aged 50 to 79 years at enrollment, with a normal body mass index and no history of CVD. The HLI score was categorized into quintiles. We estimated multivariable adjusted hazard ratios (HR) and 95% CIs for the association of HLI with risk of CVD and CVD subtypes using Cox regression models. A total of 3821 cases of incident CVD were ascertained during a median follow-up of 20.1 years. Compared with the lowest quintile (unhealthiest lifestyle), higher HLI quintiles showed inverse associations with the risk of CVD (HRquintile-2=0.74 [95% CI, 0.67-0.81]; HRquintile-3=0.66 [95% CI, 0.60-0.72]; HRquintile-4=0.57 [95% CI, 0.51-0.63]; and HRquintile-5=0.48 [95% CI, 0.43-0.54], P-trend=<0.001). HLI was also inversely associated with risks of stroke, coronary heart disease, myocardial infarction, angina, and coronary revascularization. Subgroup analyses, stratified by age (≤63 years vs >63 years), body mass index (

Submitochondrial Protein Translocation Upon Stress Inhibits Thermogenic Energy Expenditure.

Mitochondria-rich brown adipocytes dissipate cellular fuel as heat by thermogenic energy expenditure (TEE). Prolonged nutrient excess or cold exposure impair TEE and contribute to the pathogenesis of obesity, but the mechanisms remain incompletely understood. Here we report that stress-induced proton leak into the matrix interface of mitochondrial innermembrane (IM) mobilizes a group of proteins from IM into matrix, which in turn alter mitochondrial bioenergetics. We further determine a smaller subset that correlates with obesity in human subcutaneous adipose tissue. We go on to show that the top factor on this short list, acyl-CoA thioesterase 9 (ACOT9), migrates from the IM into the matrix upon stress where it enzymatically deactivates and prevents the utilization of acetyl-CoA in TEE. The loss of ACOT9 protects mice against the complications of obesity by maintaining unobstructed TEE. Overall, our results introduce aberrant protein translocation as a strategy to identify pathogenic factors. One-Sentence Summary: Thermogenic stress impairs mitochondrial energy utilization by forcing translocation of IM-bound proteins into the matrix.

Obesity alters monocyte developmental trajectories to enhance metastasis.

Obesity is characterized by chronic systemic inflammation and enhances cancer metastasis and mortality. Obesity promotes breast cancer metastasis to lung in a neutrophil-dependent manner; however, the upstream regulatory mechanisms of this process remain unknown. Here, we show that obesity-induced monocytes underlie neutrophil activation and breast cancer lung metastasis. Using mass cytometry, obesity favors the expansion of myeloid lineages while restricting lymphoid cells within the peripheral blood. RNA sequencing and flow cytometry revealed that obesity-associated monocytes resemble professional antigen-presenting cells due to a shift in their development and exhibit enhanced MHCII expression and CXCL2 production. Monocyte induction of the CXCL2-CXCR2 axis underlies neutrophil activation and release of neutrophil extracellular traps to promote metastasis, and enhancement of this signaling axis is observed in lung metastases from obese cancer patients. Our findings provide mechanistic insight into the relationship between obesity and cancer by broadening our understanding of the interactive role that myeloid cells play in this process.

Translating energy balance research from the bench to the clinic to the community: Parallel animal-human studies in cancer.

Advances in energy balance and cancer research to date have largely occurred in siloed work in rodents or patients. However, substantial benefit can be derived from parallel studies in which animal models inform the design of clinical and population studies or in which clinical observations become the basis for animal studies. The conference Translating Energy Balance from Bench to Communities: Application of Parallel Animal-Human Studies in Cancer, held in July 2021, convened investigators from basic, translational/clinical, and population science research to share knowledge, examples of successful parallel studies, and strong research to move the field of energy balance and cancer toward practice changes. This review summarizes key topics discussed to advance research on the role of energy balance, including physical activity, body composition, and dietary intake, on cancer development, cancer outcomes, and healthy survivorship.

Microbes Contribute to Chemopreventive Efficacy, Intestinal Tumorigenesis, and the Metabolome.

Bacteria are believed to play an important role in intestinal tumorigenesis and contribute to both gut luminal and circulating metabolites. Celecoxib, a selective cyclooxygenase-2 inhibitor, alters gut bacteria and metabolites in association with suppressing the development of intestinal polyps in mice. The current study sought to evaluate whether celecoxib exerts its chemopreventive effects, in part, through intestinal bacteria and metabolomic alterations. Using ApcMin/+ mice, we demonstrated that treatment with broad-spectrum antibiotics (ABx) reduced abundance of gut bacteria and attenuated the ability of celecoxib to suppress intestinal tumorigenesis. Use of ABx also impaired celecoxib's ability to shift microbial populations and gut luminal and circulating metabolites. Treatment with ABx alone markedly reduced tumor number and size in ApcMin/+ mice, in conjunction with profoundly altering the metabolite profiles of the intestinal lumen and blood. Many of the metabolite changes in the gut and circulation overlapped and included shifts in microbially derived metabolites. To complement these findings in mice, we evaluated the effects of ABx on circulating metabolites in patients with colon cancer. This showed that ABx treatment led to a shift in blood metabolites, including several that were of bacterial origin. Importantly, changes in metabolites in patients given ABx overlapped with alterations found in mice that also received ABx. Taken together, these findings suggest a potential role for bacterial metabolites in mediating both the chemopreventive effects of celecoxib and intestinal tumor growth. PREVENTION RELEVANCE: This study demonstrates novel mechanisms by which chemopreventive agents exert their effects and gut microbiota impact intestinal tumor development. These findings have the potential to lead to improved cancer prevention strategies by modulating microbes and their metabolites.

Gut microbiota-derived metabolites confer protection against SARS-CoV-2 infection.

The gut microbiome is intricately coupled with immune regulation and metabolism, but its role in Coronavirus Disease 2019 (COVID-19) is not fully understood. Severe and fatal COVID-19 is characterized by poor anti-viral immunity and hypercoagulation, particularly in males. Here, we define multiple pathways by which the gut microbiome protects mammalian hosts from SARS-CoV-2 intranasal infection, both locally and systemically, via production of short-chain fatty acids (SCFAs). SCFAs reduced viral burdens in the airways and intestines by downregulating the SARS-CoV-2 entry receptor, angiotensin-converting enzyme 2 (ACE2), and enhancing adaptive immunity via GPR41 and 43 in male animals. We further identify a novel role for the gut microbiome in regulating systemic coagulation response by limiting megakaryocyte proliferation and platelet turnover via the Sh2b3-Mpl axis. Taken together, our findings have unraveled novel functions of SCFAs and fiber-fermenting gut bacteria to dampen viral entry and hypercoagulation and promote adaptive antiviral immunity.

High-Fat Diet-Induced Obesity Alters Dendritic Cell Homeostasis by Enhancing Mitochondrial Fatty Acid Oxidation.

Obesity is associated with increased cancer risk and weak responses to vaccination and sepsis treatment. Although dendritic cells (DCs) are fundamental for the initiation and maintenance of competent immune responses against pathogens and tumors, how obesity alters the normal physiology of these myeloid cells remains largely unexplored. In this study, we report that obesity caused by prolonged high-fat diet feeding disrupts the metabolic and functional status of mouse splenic DCs (SpDCs). High-fat diet-induced obesity drastically altered the global transcriptional profile of SpDCs, causing severe changes in the expression of gene programs implicated in lipid metabolism and mitochondrial function. SpDCs isolated from obese mice demonstrated enhanced mitochondrial respiration provoked by increased fatty acid oxidation (FAO), which drove the intracellular accumulation of reactive oxygen species that impaired Ag presentation to T cells. Accordingly, treatment with the FAO inhibitor etomoxir, or antioxidants such as vitamin E or N-acetyl-l-cysteine, restored the Ag-presenting capacity of SpDCs isolated from obese mice. Our findings reveal a major detrimental effect of obesity in DC physiology and suggest that controlling mitochondrial FAO or reactive oxygen species overproduction may help improve DC function in obese individuals.

Weight Loss and/or Sulindac Mitigate Obesity-associated Transcriptome, Microbiome, and Protumor Effects in a Murine Model of Colon Cancer.

Obesity is associated with an increased risk of colon cancer. Our current study examines whether weight loss and/or treatment with the NSAID sulindac suppresses the protumor effects of obesity in a mouse model of colon cancer. Azoxymethane-treated male FVB/N mice were fed a low-fat diet (LFD) or high-fat diet (HFD) for 15 weeks, then HFD mice were randomized to remain on HFD (obese) or switch to LFD [formerly obese (FOb-LFD)]. Within the control (LFD), obese, and FOb-LFD groups, half the mice started sulindac treatment (140 ppm in the diet). All mice were euthanized 7 weeks later. FOb-LFD mice had intermediate body weight levels, lower than obese but higher than control (P < 0.05). Sulindac did not affect body weight. Obese mice had greater tumor multiplicity and burden than all other groups (P < 0.05). Transcriptomic profiling indicated that weight loss and sulindac each modulate the expression of tumor genes related to invasion and may promote a more antitumor immune landscape. Furthermore, the fecal microbes Coprobacillus, Prevotella, and Akkermansia muciniphila were positively correlated with tumor multiplicity and reduced by sulindac in obese mice. Coprobacillus abundance was also decreased in FOb-LFD mice. In sum, weight loss and sulindac treatment, alone and in combination, reversed the effects of chronic obesity on colon tumor multiplicity and burden. Our findings suggest that an investigation regarding the effects of NSAID treatment on colon cancer risk and/or progression in obese individuals is warranted, particularly for those unable to achieve moderate weight loss. PREVENTION RELEVANCE: Obesity is a colon cancer risk and/or progression factor, but the underlying mechanisms are incompletely understood. Herein we demonstrate that obesity enhances murine colon carcinogenesis and expression of numerous tumoral procancer and immunosuppressive pathways. Moreover, we establish that weight loss via LFD and/or the NSAID sulindac mitigate procancer effects of obesity.