Exercise—A Panacea of Metabolic Dysregulation in Cancer: Physiological and Molecular Insights

Metabolic dysfunction is a comorbidity of many types of cancers. Disruption of glucose metabolism is of concern, as it is associated with higher cancer recurrence rates and reduced survival. Current evidence suggests many health benefits from exercise during and after cancer treatment, yet only a limited number of studies have addressed the effect of exercise on cancer-associated disruption of metabolism. In this review, we draw on studies in cells, rodents, and humans to describe the metabolic dysfunctions observed in cancer and the tissues involved. We discuss how the known effects of acute exercise and exercise training observed in healthy subjects could have a positive outcome on mechanisms in people with cancer, namely: insulin resistance, hyperlipidemia, mitochondrial dysfunction, inflammation, and cachexia. Finally, we compile the current limited knowledge of how exercise corrects metabolic control in cancer and identify unanswered questions for future research

NOX2 deficiency exacerbates diet-induced obesity and impairs molecular training adaptations in skeletal muscle

The production of reactive oxygen species (ROS) by NADPH oxidase (NOX) 2 has been linked to both insulin resistance and exercise training adaptations in skeletal muscle. This study explores the previously unexamined role of NOX2 in the interplay between diet-induced insulin resistance and exercise training (ET). Using a mouse model that harbors a point mutation in the essential NOX2 regulatory subunit, p47phox (Ncf1*), we investigated the impact of this mutation on various metabolic adaptations. Wild-type (WT) and Ncf1* mice were assigned to three groups: chow diet, 60% energy fat diet (HFD), and HFD with access to running wheels (HFD + E). After a 16-week intervention, a comprehensive phenotypic assessment was performed, including body composition, glucose tolerance, energy intake, muscle insulin signaling, redox-related proteins, and mitochondrial adaptations. The results revealed that NOX2 deficiency exacerbated the impact of HFD on body weight, body composition, and glucose intolerance. Moreover, in Ncf1* mice, ET did not improve glucose tolerance or increase muscle cross-sectional area. ET normalized body fat independently of genotype. The lack of NOX2 activity during ET reduced several metabolic adaptations in skeletal muscle, including insulin signaling and expression of Hexokinase II and oxidative phosphorylation complexes. In conclusion, these findings suggest that NOX2 mediates key beneficial effects of exercise training in the context of diet-induced obesity

Insulin resistance in patients with cancer: a systematic review and meta-analysis

Insulin resistance is a critical cause of metabolic dysfunctions. Metabolic dysfunction is common in patients with cancer and is associated with higher cancer recurrence rates and reduced overall survival. Yet, insulin resistance is rarely considered in the clinic and thus it is uncertain how frequently this condition occurs in patients with cancer. To address this knowledge gap, we performed a systematic review and a meta-analysis guided by the Preferred Items for Systematic Review and Meta-Analyses (PRISMA) statement. We included studies assessing insulin resistance in patients with various cancer diagnoses, using the gold-standard hyperinsulinemic–euglycemic clamp method. Studies eligible for inclusion were as follows: (1) included cancer patients older than 18 years of age; (2) included an age-matched control group consisting of individuals without cancer or other types of neoplasms; (3) measured insulin sensitivity using the hyperinsulinemic–euglycemic clamp method. We searched the databases MEDLINE, Embase, and Cochrane Central Register of Controlled Trials for articles published from database inception through March 2023 with no language restriction, supplemented by backward and forward citation searching. Bias was assessed using funnel plot. Fifteen studies satisfied the criteria. The mean insulin-stimulated rate of glucose disposal (Rd) was 7.5 mg/kg/min in control subjects (n = 154), and 4.7 mg/kg/min in patients with a cancer diagnosis (n = 187). Thus, the Rd mean difference was −2.61 mg/kg/min [95% confidence interval, −3.04; −2.19], pp=.24). These findings suggest that patients with a cancer diagnosis are markedly insulin resistant. As metabolic dysfunction in patients with cancer associates with increased recurrence and reduced overall survival, future studies should address if ameliorating insulin resistance in this population can improve these outcomes thereby improving patient care.Key pointsMetabolic dysfunction increases cancer recurrence rates and reduces survival for patients with cancer.Insulin resistance is a critical cause of metabolic dysfunctions.To date, no comprehensive compilation of research investigating insulin resistance in cancer patients has been produced.In this meta-analysis, we found that patients with various cancers were markedly insulin-resistant. Metabolic dysfunction increases cancer recurrence rates and reduces survival for patients with cancer. Insulin resistance is a critical cause of metabolic dysfunctions. To date, no comprehensive compilation of research investigating insulin resistance in cancer patients has been produced. In this meta-analysis, we found that patients with various cancers were markedly insulin-resistant.</p

Adenosine monophosphate‐activated protein kinase is elevated in human cachectic muscle and prevents cancer‐induced metabolic dysfunction in mice

Abstract Background Metabolic dysfunction and cachexia are associated with poor cancer prognosis. With no pharmacological treatments, it is crucial to define the molecular mechanisms causing cancer‐induced metabolic dysfunction and cachexia. Adenosine monophosphate‐activated protein kinase (AMPK) connects metabolic and muscle mass regulation. As AMPK could be a potential treatment target, it is important to determine the function for AMPK in cancer‐associated metabolic dysfunction and cachexia. We therefore established AMPK's roles in cancer‐associated metabolic dysfunction, insulin resistance and cachexia. Methods In vastus lateralis muscle biopsies from n = 26 patients with non‐small cell lung cancer (NSCLC), AMPK signalling and protein content were examined by immunoblotting. To determine the role of muscle AMPK, male mice overexpressing a dominant‐negative AMPKα2 (kinase‐dead [KiDe]) specifically in striated muscle were inoculated with Lewis lung carcinoma (LLC) cells (wild type [WT]: n = 27, WT + LLC: n = 34, mAMPK‐KiDe: n = 23, mAMPK‐KiDe + LLC: n = 38). Moreover, male LLC‐tumour‐bearing mice were treated with (n = 10)/without (n = 9) 5‐aminoimidazole‐4‐carboxamide ribonucleotide (AICAR) to activate AMPK for 13 days. Littermate mice were used as controls. Metabolic phenotyping of mice was performed via indirect calorimetry, body composition analyses, glucose and insulin tolerance tests, tissue‐specific 2‐[3H]deoxy‐d‐glucose (2‐DG) uptake and immunoblotting. Results Patients with NSCLC presented increased muscle protein content of AMPK subunits α1, α2, β2, γ1 and γ3 ranging from +27% to +79% compared with control subjects. In patients with NSCLC, AMPK subunit protein content correlated with weight loss (α1, α2, β2 and γ1), fat‐free mass (α1, β2 and γ1) and fat mass (α1 and γ1). Tumour‐bearing mAMPK‐KiDe mice presented increased fat loss and glucose and insulin intolerance. LLC in mAMPK‐KiDe mice displayed lower insulin‐stimulated 2‐DG uptake in skeletal muscle (quadriceps: −35%, soleus: −49%, extensor digitorum longus: −48%) and the heart (−29%) than that in non‐tumour‐bearing mice. In skeletal muscle, mAMPK‐KiDe abrogated the tumour‐induced increase in insulin‐stimulated TBC1D4thr642 phosphorylation. The protein content of TBC1D4 (+26%), pyruvate dehydrogenase (PDH; +94%), PDH kinases (+45% to +100%) and glycogen synthase (+48%) was increased in skeletal muscle of tumour‐bearing mice in an AMPK‐dependent manner. Lastly, chronic AICAR treatment elevated hexokinase II protein content and normalized phosphorylation of p70S6Kthr389 (mTORC1 substrate) and ACCser212 (AMPK substrate) and rescued cancer‐induced insulin intolerance. Conclusions Protein contents of AMPK subunits were upregulated in skeletal muscle of patients with NSCLC. AMPK activation seemed protectively inferred by AMPK‐deficient mice developing metabolic dysfunction in response to cancer, including AMPK‐dependent regulation of multiple proteins crucial for glucose metabolism. These observations highlight the potential for targeting AMPK to counter cancer‐associated metabolic dysfunction and possibly cachexia

Glucometabolic consequences of acute and prolonged inhibition of fatty acid oxidation

Excessive circulating FAs have been proposed to promote insulin resistance (IR) of glucose metabolism by increasing the oxidation of FAs over glucose. Therefore, inhibition of FA oxidation (FAOX) has been suggested to ameliorate IR. However, prolonged inhibition of FAOX would presumably cause lipid accumulation and thereby promote lipotoxicity. To understand the glycemic consequences of acute and prolonged FAOX inhibition, we treated mice with the carnitine palmitoyltransferase 1 (CPT-1) inhibitor, etomoxir (eto), in combination with short-term 45% high fat diet feeding to increase FA availability. Eto acutely increased glucose oxidation and peripheral glucose disposal, and lowered circulating glucose, but this was associated with increased circulating FAs and triacylglycerol accumulation in the liver and heart within hours. Several days of FAOX inhibition by daily eto administration induced hepatic steatosis and glucose intolerance, specific to CPT-1 inhibition by eto. Lower whole-body insulin sensitivity was accompanied by reduction in brown adipose tissue (BAT) uncoupling protein 1 (UCP1) protein content, diminished BAT glucose clearance, and increased hepatic glucose production. Collectively, these data suggest that pharmacological inhibition of FAOX is not a viable strategy to treat IR, and that sufficient rates of FAOX are required for maintaining liver and BAT metabolic function

TNIK is a conserved regulator of glucose and lipid metabolism in obesity

Obesity and type 2 diabetes (T2D) are growing health challenges with unmet treatment needs. Traf2- and NCK-interacting protein kinase (TNIK) is a recently identified obesity- and T2D-associated gene with unknown functions. We show that TNIK governs lipid and glucose homeostasis in Drosophila and mice. Loss of the Drosophila ortholog of TNIK, misshapen, altered the metabolite profiles and impaired de novo lipogenesis in high sugar-fed larvae. Tnik knockout mice exhibited hyperlocomotor activity and were protected against diet-induced fat expansion, insulin resistance, and hepatic steatosis. The improved lipid profile of Tnik knockout mice was accompanied by enhanced skeletal muscle and adipose tissue insulin-stimulated glucose uptake and glucose and lipid handling. Using the T2D Knowledge Portal and the UK Biobank, we observed associations of TNIK variants with blood glucose, HbA1c, body mass index, body fat percentage, and feeding behavior. These results define an untapped paradigm of TNIK-controlled glucose and lipid metabolism.Peer reviewe

Pulmonary exposure to carbon black by inhalation or instillation in pregnant mice: Effects on liver DNA strand breaks in dams and offspring

Effects of maternal pulmonary exposure to carbon black (Printex 90) on gestation, lactation and DNA strand breaks were evaluated. Time-mated C57BL/6BomTac mice were exposed by inhalation to 42 mg/m(3) Printex 90 for 1 h/day on gestation days (GD) 8-18, or by four intratracheal instillations on GD 7, 10, 15 and 18, with total doses of 11, 54 and 268 (μg/animal. Dams were monitored until weaning and some offspring until adolescence. Inflammation was assessed in maternal bronchoalveolar lavage (BAL) 3-5 days after exposure, and at weaning. Levels of DNA strand breaks were assessed in maternal BAL cells and liver, and in offspring liver. Persistent lung inflammation was observed in exposed mothers. Inhalation exposure induced more DNA strand breaks in the liver of mothers and their offspring, whereas intratracheal instillation did not. Neither inhalation nor instillation affected gestation and lactation. Maternal inhalation exposure to Printex 90-induced liver DNA damage in the mothers and the in utero exposed offspring