Mass extinctions occur frequently in natural history. While studies of animals that became extinct can be informative, it is the survivors that provide clues for mechanisms of adaptation when ...conditions are adverse. Here, we describe a survival pathway used by many species as a means for providing adequate fuel and water, while also providing protection from a decrease in oxygen availability. Fructose, whether supplied in the diet (primarily fruits and honey), or endogenously (via activation of the polyol pathway), preferentially shifts the organism towards the storing of fuel (fat, glycogen) that can be used to provide energy and water at a later date. Fructose causes sodium retention and raises blood pressure and likely helped survival in the setting of dehydration or salt deprivation. By shifting energy production from the mitochondria to glycolysis, fructose reduced oxygen demands to aid survival in situations where oxygen availability is low. The actions of fructose are driven in part by vasopressin and the generation of uric acid. Twice in history, mutations occurred during periods of mass extinction that enhanced the activity of fructose to generate fat, with the first being a mutation in vitamin C metabolism during the Cretaceous–Paleogene extinction (65 million years ago) and the second being a mutation in uricase that occurred during the Middle Miocene disruption (12–14 million years ago). Today, the excessive intake of fructose due to the availability of refined sugar and high‐fructose corn syrup is driving ‘burden of life style’ diseases, including obesity, diabetes and high blood pressure.
Content List ‐ This is an article from the symposium: “Bioinspirational medicine”.
Dietary guidelines for obesity typically focus on three food groups (carbohydrates, fat, and protein) and caloric restriction. Intake of noncaloric nutrients, such as salt, are rarely discussed. ...However, recently high salt intake has been reported to predict the development of obesity and insulin resistance. The mechanism for this effect is unknown. Here we show that high intake of salt activates the aldose reductase–fructokinase pathway in the liver and hypothalamus, leading to endogenous fructose production with the development of leptin resistance and hyperphagia that cause obesity, insulin resistance, and fatty liver. A high-salt diet was also found to predict the development of diabetes and nonalcoholic fatty liver disease in a healthy population. These studies provide insights into the pathogenesis of obesity and diabetes and raise the potential for reduction in salt intake as an additional interventional approach for reducing the risk for developing obesity and metabolic syndrome.
Intake of fructose-containing sugars is strongly associated with metabolic syndrome. Compared with other sugars, dietary fructose is uniquely metabolized by fructokinase. However, the tissue-specific ...role of fructokinase in sugar-induced metabolic syndrome, and the specific roles of glucose and fructose in driving it, is not fully understood. Here, we show that in mice receiving excess fructose-glucose solutions, whole-body deletion of fructokinase, and thus full blockade of fructose metabolism, is sufficient to prevent metabolic syndrome. This protection is not only due to reduced fructose metabolism, but also due to decreased sugar intake. Furthermore, by using tissue-specific fructokinase-deficient mice, we determined that while sugar intake is controlled by intestinal fructokinase activity, metabolic syndrome is driven by fructose metabolism in the liver. Our findings show a two-pronged role for fructose metabolism in sugar-induced metabolic syndrome, one arm via the intestine that mediates sugar intake and a second arm in the liver that drives metabolic dysfunction.
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•Fructose metabolism is necessary for sugar-induced obesity and metabolic syndrome•Fructose induces tissue-dependent effects on sugar intake and metabolic dysfunction•Sugar intake and preference is mediated by intestinal fructose metabolism•Sugar-induced metabolic syndrome is mediated by hepatic fructose metabolism
Here, Andres-Hernando et al. demonstrate that fructose exerts differential physiological effects depending on the tissue where it is metabolized. By manipulating the expression of fructokinase, a key fructose metabolizing enzyme, they show that fructose acts in the gut to regulate sweet taste preference and sugar intake, while its excess catabolism in the liver drives the majority of metabolic syndrome development.
In this narrative review, we present the hypothesis that key mutations in two genes, occurring 15 and 10 million years ago (MYA), were individually and then collectively adaptive for ancestral humans ...during periods of starvation, but are maladaptive in modern civilization (i.e., “thrifty genes”), with the consequence that these genes not only increase our risk today for obesity, but also for alcoholism. Both mutations occurred when ancestral apes were experiencing loss of fruit availability during periods of profound climate change or environmental upheaval. The silencing of uricase (urate oxidase) activity 15 MYA enhanced survival by increasing the ability for fructose present in dwindling fruit to be stored as fat, a consequence of enhanced uric acid production during fructose metabolism that stimulated lipogenesis and blocked fatty acid oxidation. Likewise, a mutation in class IV alcohol dehydrogenase ~10 MYA resulted in a remarkable 40‐fold increase in the capacity to oxidize ethanol (EtOH), which allowed our ancestors to ingest fallen, fermenting fruit. In turn, the EtOH ingested could activate aldose reductase that stimulates the conversion of glucose to fructose, while uric acid produced during EtOH metabolism could further enhance fructose production and metabolism. By aiding survival, these mutations would have allowed our ancestors to generate more fat, primarily from fructose, to survive changing habitats due to the Middle Miocene disruption and also during the late‐Miocene aridification of East Africa. Unfortunately, the enhanced ability to metabolize and utilize EtOH may now be acting to increase our risk for alcoholism, which may be yet another consequence of once‐adaptive thrifty genes.
We review mutations for uricase and class IV alcohol dehydrogenase and present the hypothesis that they were adaptive for survival during periods of starvation in our past—allowing ancestral humans to generate more fat, primarily from fructose—but are maladaptive in modern civilization (i.e., “thrifty genes”), with the consequence that these genes not only increase our risk today for obesity, but also for alcoholism. Thus, alcoholism may reflect yet another contemporary and adverse consequence of once‐adaptive selection on thrifty genes.
Objective
Whether obesity without metabolic syndrome (i.e., “metabolically healthy” obesity) confers similar or less metabolic risk remains controversial.
Methods
A retrospective 5‐year cohort study ...of 9,721 Japanese subjects (48.5 ± 10.5 years, 4,160 men) was conducted in 2004 and reevaluated 5 years later. Subjects were excluded if they were hypertensive or diabetic or were receiving medications for dyslipidemia and/or gout or hyperuricemia in 2004. Study subjects were categorized according to baseline BMI ≥ 25 kg/m2 (overweight/obesity) and < 25 kg/m2 (lean/normal weight) and also whether they had metabolic syndrome. The cumulative incidence of hypertension and diabetes over 5 years between groups was assessed. A second analysis evaluated whether baseline hyperuricemia provided additional risk.
Results
Subjects with overweight/obesity but without metabolic syndrome carried increased cumulative incidence of hypertension (14.6% vs. 7.2%, P < 0.001) and diabetes (2.6% vs. 1.1%, P = 0.004) over 5 years compared to lean/normal subjects without metabolic syndrome. Overweight/obesity conferred an increased risk for diabetes even in individuals with normal fasting blood glucose. Hyperuricemia became an independent risk factor for developing hypertension over 5 years in lean/normal subjects without metabolic syndrome. A 1 mg/dL increase in serum uric acid carried increased risk for hypertension (19%) and diabetes (27%).
Conclusions
Metabolically healthy obesity and hyperuricemia confer increased risk for hypertension and diabetes.
This paper proposes a new method to solve the multistage security-constrained transmission expansion planning problem, incorporating lines based on high-voltage alternating current (HVAC) and ...high-voltage direct current (HVDC) alternatives. A novel mixed-integer linear programming model, which incorporates transmission losses using a piecewise linearization, is presented. An efficient method to reduce the search space of the problem is developed to help in the solution process. Garver's 6-bus system and a modified Southern Brazilian system are used to show the precision and efficiency of the proposed approach. The tests are performed for cases with and without HVDC links and transmission losses. The results indicate that better expansion plans can be found by considering HVDC proposals in the expansion process. The promising trend of using HVDC lines in future networks to improve the reliability in the system is demonstrated.
Fructose Production and Metabolism in the Kidney Nakagawa, Takahiko; Johnson, Richard J; Andres-Hernando, Ana ...
Journal of the American Society of Nephrology,
05/2020, Letnik:
31, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Understanding fructose metabolism might provide insights to renal pathophysiology. To support systemic glucose concentration, the proximal tubular cells reabsorb fructose as a substrate for ...gluconeogenesis. However, in instances when fructose intake is excessive, fructose metabolism is costly, resulting in energy depletion, uric acid generation, inflammation, and fibrosis in the kidney. A recent scientific advance is the discovery that fructose can be endogenously produced from glucose under pathologic conditions, not only in kidney diseases, but also in diabetes, in cardiac hypertrophy, and with dehydration. Why humans have such a deleterious mechanism to produce fructose is unknown, but it may relate to an evolutionary benefit in the past. In this article, we aim to illuminate the roles of fructose as it relates to gluconeogenesis and fructoneogenesis in the kidney.
Climate change has led to significant rise of 0.8°C-0.9°C in global mean temperature over the last century and has been linked with significant increases in the frequency and severity of heat waves ...(extreme heat events). Climate change has also been increasingly connected to detrimental human health. One of the consequences of climate-related extreme heat exposure is dehydration and volume loss, leading to acute mortality from exacerbations of pre-existing chronic disease, as well as from outright heat exhaustion and heat stroke. Recent studies have also shown that recurrent heat exposure with physical exertion and inadequate hydration can lead to CKD that is distinct from that caused by diabetes, hypertension, or GN. Epidemics of CKD consistent with heat stress nephropathy are now occurring across the world. Here, we describe this disease, discuss the locations where it appears to be manifesting, link it with increasing temperatures, and discuss ongoing attempts to prevent the disease. Heat stress nephropathy may represent one of the first epidemics due to global warming. Government, industry, and health policy makers in the impacted regions should place greater emphasis on occupational and community interventions.
Dietary, fructose-containing sugars have been strongly associated with the development of nonalcoholic fatty liver disease (NAFLD). Recent studies suggest that fructose also can be produced via the ...polyol pathway in the liver, where it may induce hepatic fat accumulation. Moreover, fructose metabolism yields uric acid, which is highly associated with NAFLD. Here, using biochemical assays, reporter gene expression, and confocal fluorescence microscopy, we investigated whether uric acid regulates aldose reductase, a key enzyme in the polyol pathway. We evaluated whether soluble uric acid regulates aldose reductase expression both in cultured hepatocytes (HepG2 cells) and in the liver of hyperuricemic rats and whether this stimulation is associated with endogenous fructose production and fat accumulation. Uric acid dose-dependently stimulated aldose reductase expression in the HepG2 cells, and this stimulation was associated with endogenous fructose production and triglyceride accumulation. This stimulatory mechanism was mediated by uric acid–induced oxidative stress and stimulation of the transcription factor nuclear factor of activated T cells 5 (NFAT5). Uric acid also amplified the effects of elevated glucose levels to stimulate hepatocyte triglyceride accumulation. Hyperuricemic rats exhibited elevated hepatic aldose reductase expression, endogenous fructose accumulation, and fat buildup that was significantly reduced by co-administration of the xanthine oxidase inhibitor allopurinol. These results suggest that uric acid generated during fructose metabolism may act as a positive feedback mechanism that stimulates endogenous fructose production by stimulating aldose reductase in the polyol pathway. Our findings suggest an amplifying mechanism whereby soft drinks rich in glucose and fructose can induce NAFLD.
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