Continuously rising trends in obesity-related malignancies render this disease spectrum a public health priority. Worldwide, the burden of cancer attributable to obesity, expressed as population attributable fraction, is 11.9% in men and 13.1% in women. There is convincing evidence that excess body weight is associated with an increased risk for cancer of at least 13 anatomic sites, including endometrial, esophageal, renal and pancreatic adenocarcinomas; hepatocellular carcinoma; gastric cardia cancer; meningioma; multiple myeloma; colorectal, postmenopausal breast, ovarian, gallbladder and thyroid cancers. We first synopsize current epidemiologic evidence; the obesity paradox in cancer risk and mortality; the role of weight gain and weight loss in the modulation of cancer risk; reliable somatometric indicators for obesity and cancer research; and gender differences in obesity related cancers. We critically summarize emerging biological mechanisms linking obesity to cancer encompassing insulin resistance and abnormalities of the IGF-I system and signaling; sex hormones biosynthesis and pathway; subclinical chronic low-grade inflammation and oxidative stress; alterations in adipokine pathophysiology; factors deriving from ectopic fat deposition; microenvironment and cellular perturbations including vascular perturbations, epithelial-mesenchymal transition, endoplasmic reticulum stress and migrating adipose progenitor cells; disruption of circadian rhythms; dietary nutrients; factors with potential significance such as the altered intestinal microbiome; and mechanic factors in obesity and cancer. Future perspectives regarding prevention, diagnosis and therapeutics are discussed. The aim of this review is to investigate how the interplay of these main potential mechanisms and risk factors, exerts their effects on target tissues provoking them to acquire a cancerous phenotype.

Obesity and cancer risk: Emerging biological mechanisms and perspectives.

The vulnerability of cancer cells to nutrient deprivation and their dependency on specific metabolites are emerging hallmarks of cancer. Fasting or fasting-mimicking diets (FMDs) lead to wide alterations in growth factors and in metabolite levels, generating environments that can reduce the capability of cancer cells to adapt and survive and thus improving the effects of cancer therapies. In addition, fasting or FMDs increase resistance to chemotherapy in normal but not cancer cells and promote regeneration in normal tissues, which could help prevent detrimental and potentially life-threatening side effects of treatments. While fasting is hardly tolerated by patients, both animal and clinical studies show that cycles of low-calorie FMDs are feasible and overall safe. Several clinical trials evaluating the effect of fasting or FMDs on treatment-emergent adverse events and on efficacy outcomes are ongoing. We propose that the combination of FMDs with chemotherapy, immunotherapy or other treatments represents a potentially promising strategy to increase treatment efficacy, prevent resistance acquisition and reduce side effects.

Fasting and cancer: molecular mechanisms and clinical application

Optimising training and performance through nutrition strategies is central to supporting elite sportspeople, much of which has focused on manipulating the relative intake of carbohydrate and fat and their contributions as fuels for energy provision. The ketone bodies, namely acetoacetate, acetone and β-hydroxybutyrate (βHB), are produced in the liver during conditions of reduced carbohydrate availability and serve as an alternative fuel source for peripheral tissues including brain, heart and skeletal muscle. Ketone bodies are oxidised as a fuel source during exercise, are markedly elevated during the post-exercise recovery period, and the ability to utilise ketone bodies is higher in exercise-trained skeletal muscle. The metabolic actions of ketone bodies can alter fuel selection through attenuating glucose utilisation in peripheral tissues, anti-lipolytic effects on adipose tissue, and attenuation of proteolysis in skeletal muscle. Moreover, ketone bodies can act as signalling metabolites, with βHB acting as an inhibitor of histone deacetylases, an important regulator of the adaptive response to exercise in skeletal muscle. Recent development of ketone esters facilitates acute ingestion of βHB that results in nutritional ketosis without necessitating restrictive dietary practices. Initial reports suggest this strategy alters the metabolic response to exercise and improves exercise performance, while other lines of evidence suggest roles in recovery from exercise. The present review focuses on the physiology of ketone bodies during and after exercise and in response to training, with specific interest in exploring the physiological basis for exogenous ketone supplementation and potential benefits for performance and recovery in athletes.

Metabolism of ketone bodies during exercise and training: physiological basis for exogenous supplementation

β-hydroxybutyrate: much more than a metabolite.

Obesity is reaching epidemic proportions and is a strong risk factor for a number of cardiovascular and metabolic disorders such as hypertension, type 2 diabetes, dyslipidemia, atherosclerosis, and also certain types of cancers. Despite the constant recommendations of health care organizations regarding the importance of weight control, this goal often fails. Genetic predisposition in combination with inactive lifestyles and high caloric intake leads to excessive weight gain. Even though there may be agreement about the concept that lifestyle changes affecting dietary habits and physical activity are essential to promote weight loss and weight control, the ideal amount and type of exercise and also the ideal diet are still under debate. For many years, nutritional intervention studies have been focused on reducing dietary fat with little positive results over the long-term. One of the most studied strategies in the recent years for weight loss is the ketogenic diet. Many studies have shown that this kind of nutritional approach has a solid physiological and biochemical basis and is able to induce effective weight loss along with improvement in several cardiovascular risk parameters. This review discusses the physiological basis of ketogenic diets and the rationale for their use in obesity, discussing the strengths and the weaknesses of these diets together with cautions that should be used in obese patients.

https://www.mdpi.com/1660-4601/11/2/2092/pdf

Ketogenic Diet for Obesity: Friend or Foe?

Very-low-carbohydrate diets or ketogenic diets have been in use since the 1920s as a therapy for epilepsy and can, in some cases, completely remove the need for medication. From the 1960s onwards they have become widely known as one of the most common methods for obesity treatment. Recent work over the last decade or so has provided evidence of the therapeutic potential of ketogenic diets in many pathological conditions, such as diabetes, polycystic ovary syndrome, acne, neurological diseases, cancer and the amelioration of respiratory and cardiovascular disease risk factors. The possibility that modifying food intake can be useful for reducing or eliminating pharmaceutical methods of treatment, which are often lifelong with significant side effects, calls for serious investigation. This review revisits the meaning of physiological ketosis in the light of this evidence and considers possible mechanisms for the therapeutic actions of the ketogenic diet on different diseases. The present review also questions whether there are still some preconceived ideas about ketogenic diets, which may be presenting unnecessary barriers to their use as therapeutic tools in the physician’s hand.

/pdf/beyond-weight-loss-a-review-of-the-therapeutic-uses-of-very-99xoy1xg4k.pdf

Beyond weight loss: a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets

The aim of this study was to measure the flow and volume dependence of both the ohmic and the viscoelastic pressure dissipations of the normal rat respiratory system separately during inflation and deflation. The study was conducted in the Respiratory Physiology Laboratory in our institution. Measurements were obtained for Seven albino Wistar rats of both sexes by using the flow interruption method during constant flow inflations and deflations. Measurements included anesthesia induction, tracheostomy and positioning of a tracheal cannula, positive pressure ventilation, constant flow respiratory system inflations and deflations at two different volumes and flows. The ohmic resistance exhibited volume and flow dependence, decreasing with lung volume and increasing with flow rate, during both inflation and deflation. The stress relaxation-related viscoelastic resistance also exhibited volume and flow dependence. It decreased with the flow rate at a constant lung volume during both inflation and deflation, but exhibited a different behavior with the lung volume at a constant flow rate (i.e., increased during inflations and decreased during deflations). Thus, stress relaxation in the rat lungs exhibited a hysteretic behavior. The observed flow and volume dependence of respiratory system resistance may be predicted by an equation derived from a model of the respiratory system that consists of two distinct compartments. The equation agrees well with the experimental data and indicates that the loading time is the critical parameter on which stress relaxation depends, during both lung inflation and deflation.

Flow and Volume Dependence of Rat Airway Resistance During Constant Flow Inflation and Deflation

The mechanical characteristics of respiratory system tissues include visco-elastic behaviour. In particular, after mechanical unloading, i.e., a reduction in respiratory system volume, the lower stress achieved slowly increases, approaching higher constant value, due to visco-elastic stress recovery. We performed experiments in which constant deflation flow arrest was applied in rats to study the successive pressure-time course, which defines the visco-elastic stress recovery. To investigate the possible effects of temperature changes, measurements were performed at two body temperatures, 36.6 ± 0.3 and 39.0 ± 0.1 °C. We found that stress recovery is reduced by increasing body temperature. Pressure-time curves after deflation arrest were fitted by specific mathematical model, and a good agreement was found. Model parameters exhibited significant changes with body temperature variations, suggesting that temperaturedependent micro-structural rearrangement phenomena in the tissues of alveolar wall were involved in the stress recovery decrement with body temperature increase. Thus, visco-elastic phenomena in respiratory system tissues of mammals exhibit temperature dependence. The stress recovery changes with body temperature suggest that expiration is expected to be easier in condition of physiological body temperature than in the case of increased temperature.

http://www.actabio.pwr.wroc.pl/Vol14No3/8.pdf

The effect of body warming on respiratory system stress recovery in the rat.

We measured metabolic (oxygen uptake, carbon dioxide production, respiratory ratio), cardio-circulatory (heart rate, systolic and diastolic arterial blood pressure, rate-pressure product, an index of myocardial oxygen consumption calculated by multiplying heart rate by systolic pressure) and electromyographic (integrated electromyographic activities of two antigravitational muscles of the lower limb, soleus and gastrocnemius) variables on 12 young healthy subjects in supine and standing positions at rest. We found statistically significant increments of oxygen uptake, carbon dioxide production, heart rate and integrated electromyographic activities in standing versus supine position. Rate-pressure product increased but not significantly, and no other significant changes were detected. We conclude that postural changes influence metabolic rate, antigravitational muscle reflex activities, and heart rate. A significant positive correlation was found between oxygen uptake and carbon dioxide production and integrated electromyographic activities of antigravitational muscles, while the same was not found for cardio-circulatory variables. These results suggest that the increased metabolic rate in standing position is, at least in part, due to antigravitational muscle tone.

Body metabolic rate and electromyographic activities of antigravitational muscles in supine and standing postures

This study was designed to investigate the possible effects of acute hyperbaric hyperoxia on respiratory mechanics of anaesthetised, positive-pressure ventilated rats. We measured respiratory mechanics by the end-inflation occlusion method in nine rats previously acutely exposed to hyperbaric hyperoxia in a standard fashion. The method allows the measurements of respiratory system elastance and of both the “ohmic” and of the viscoelastic components of airway resistance, which respectively depend on the newtonian pressure dissipation due to the ohmic airway resistance to air flow, and on the viscoelastic pressure dissipation caused by respiratory system tissues stress–relaxation. The activities of inducible and endothelial NO-synthase in the lung’s tissues (iNOS and eNOS respectively) also were investigated. Data were compared with those obtained in control animals. We found that the exposure to hyperbaric hyperoxia increased respiratory system elastance and both the “ohmic” and viscoelastic components of inspiratory resistances. These changes were accompanied by increased iNOS but not eNOS activities. Hyperbaric hyperoxia was shown to acutely induce detrimental effects on respiratory mechanics. A possible causative role was suggested for increased nitrogen reactive species production because of increased iNOS activity.

Alessandro Rubini

Papers

Beyond weight loss: a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets

Flow and Volume Dependence of Rat Airway Resistance During Constant Flow Inflation and Deflation

The effect of body warming on respiratory system stress recovery in the rat.

Body metabolic rate and electromyographic activities of antigravitational muscles in supine and standing postures

The effect of acute exposure to hyperbaric oxygen on respiratory system mechanics in the rat.