Introduction

In accordance with data from the World Health Organization (WHO), diseases associated with obesity have become one of the main health problems worldwide. The number of overweight people in almost every region of the world (except in certain sub-Saharan African regions and some Asian areas) has been increasing at a constant annual rate of 0.7% since 1975 to the end of the second decade of the 21^st century (World Health Organization, 2018) Using the body mass index (BMI) scale, the WHO pointed out that in 2016, more than 39% of people older than 18 years old (more than 1,900 million) were overweight, while 13% of the world’s population (more than 650 million people) was diagnosed with obesity. Among children and teenagers within the age interval of 5-19 years and children under 5 years old, 18% (over 340 million) and 6% (more than 113 million children) were overweight, respectively (Murray, 2019; Pearlman, Obert & Casey, 2017; Stanhope, 2016) . This worldwide phenomenon in which there are more overweight than underweight people was recognized since the last third of the 20^th century, indicating that two out of the three countries in North America (namely, México and the United States), and many countries of the European Union, had the most affected population by this health crisis (Hruby & Hu, 2015; Ogden, Yanovski, Carroll & Flegal, 2007; Pereira et al., 2020; Smith & Smith, 2016).

It is generally stated that the main cause of obesity is related to an imbalance between the calories consumed and the calories expended. In accordance with WHO experts (World Health Organization, 2018), obesity problems can be explained considering that “there is an increased intake of energy-dense foods that are high in fat, along with an increase in physical inactivity due to the increasingly sedentary nature of many forms of work, changing modes of transportation, and increasing urbanization”.

However, to prevent and treat the obesity problem, experts need to clearly understand lipogenesis and lipolysis, as well as the processes that determine the formation of adipose tissue derived from both sugar-rich foods, whose main ingredient is fructose, and foods high in fat (Moran & Ladenheim, 2016; Priyadarshini & Anuradha, 2017). In other words, it is essential to understand the glucose-fatty acid cycle, also known as the Randle cycle, to recognize the causes of obesity and propose preventive and effective measures (Randle, Garland, Hales & Newsholme, 1963).

Likewise, the general population should be aware of the seventy different names given to sugar that are included in processed foods, in order to keep track of excessive carbohydrate consumption (Gómez Candela & Palma Milla, 2013; Rodríguez Delgado, 2017). It is estimated that sugar-sweetened beverages (soft drinks, juices, nectars, teas, energy drinks, yogurts, among others) are the main sources of sugar in the diet, accounting for more than 15% of the daily caloric intake. Besides, many people do not even realize that their consumption of sugar-sweetened beverages and low-nutrient density foods is much more frequent than they think (Jensen et al., 2018; Rodríguez Delgado, 2017).

This increase in sugar consumption has been associated with pathologies such as liver steatosis, type 2 diabetes mellitus, simple and combined hyperlipidemias (hypertriglyceridemia and hypercholesterolemia), cardiovascular diseases (hypertension, and heart failure) and dental caries, the latter originally described as the only disorder due to sugar consumption. Therefore, in this review we updated the information regarding the Randle cycle, proposed in 1963 (Randle et al., 1963), and the balance between the formation of acylglycerols and their breakdown (lipogenesis/lipolysis).

The Randle cycle and its association with the balance between lipogenesis and lipolysis

Postprandial state

Under hyperglycemic conditions, such as the postprandial state, insulin induces an increase in the expression of glycolytic regulatory enzymes (glucokinase; phosphofructokinase 1, PFK-1; and pyruvate kinase) and the glucose transporter GLUT 4 (Figure 1). Insulin also activates genes that code for enzymes involved in the Randle cycle (Table I), leading to an increase in the glycolytic and Krebs cycle fluxes and the stimulation of anabolic pathways, such as lipogenesis, β-reduction [synthesis of fatty acids in the cytosol catalyzed by the Fatty Acid Synthase (FAS)], phospholipogenesis and cholesterogenesis (Marcelino et al., 2013; Nakamura, Yudell & Loor, 2014; Palomer, Salvado, Barroso & Vázquez-Carrera, 2013; Possik, Madiraju & Prentki, 2017).

In terms of metabolic pathways, it can be inferred that a sugar overload in glycolysis will drive some of the glucose carbons towards dihydroxyacetone phosphate (DHAP) (Figure 1), which is involved in the formation of acylglycerols (lipogenesis) and phospholipids (phospholipogenesis) (Song, Xiaoli & Yang, 2018) (Figure 1). Therefore, glycolytic flux and anaplerotic pathways are activated in the presence of insulin (Ameer, Scandiuzzi, Hasnain, Kalbacher, & Zaidi, 2014; Bartelt et al., 2013; Summermatter et al., 2009).

Carbon overload in glycolysis is also associated with the transfer of citrate from mitochondria to the cytosol, where oxaloacetate (OAA) and acetyl-CoA are produced by the ATP citrate lyase (Figure 1). The first of these metabolites can be reduced or transaminated and returned to the mitochondrial matrix, forming part of the malate-aspartate shuttle.

Acetyl-CoA can take two pathways in the cytosol: the formation of fatty acids or the synthesis of cholesterol (Figure 1). Fatty acid formation is controlled by the FAS and the presence of allosteric regulators of the acetyl-CoA carboxylase (ACC) (Figure 1). In the presence of insulin, β-oxidation (the mitochondrial catabolic process of breaking down fatty acids) is inhibited by malonyl-CoA, stopping the transport of fatty acids into the mitochondrial matrix mediated by the fatty acid transporter Carnitine Acyltransferase 1 (CAT1) (Figure 1).

Regarding cholesterol formation, the pathway is regulated by the hydroxymethylglutaryl-CoA reductase (HMG-CoA reductase). The fate of acetyl-CoA’s carbons can be defined as tissue-dependent, and regulated by the formation of malonyl-CoA and mevalonate metabolites, which control the rate of β-reduction and cholesterogenesis, respectively (Barbosa & Siniossoglou, 2017; Kory, Farese Jr. & Walther, 2016; Mottillo et al., 2014; Rambold, Cohen & Lippincott-Schwartz, 2015).

Insulin also increases the expression of lipoprotein lipase (LPL) in the postprandial state. This allows the hydrolysis of plasma triacylglycerol (TAG) from exogenous sources (diet), found in chylomicrons, and endogenous sources (hepatic), present in the Very Low Density Lipoproteins (VLDL) (Figure 1). Proper LPL functioning is associated with adapter proteins that stabilize and activate LPL (Quiroga & Lehner, 2012), such as apoprotein C-II on the smooth and skeletal muscles, and adipose tissue (Figure 1). Also, hydrolysis of TAG is more efficient when apoprotein C-V is active.

Fasting conditions

Under fasting or starvation conditions, lipolysis in white adipocytes is increased by hormones, such as glucagon (Pereira et al., 2020) and norepinephrine, which activate the hormone-sensitive lipase (Figure 1), and decrease the activity of the enzymes that control lipid anabolism, such as HMG-CoA reductase, ACC, and LPL (Hilton, Karpe & Pinnick, 2015; Quiroga & Lehner, 2018; Rambold et al., 2015). Due to their hydrophobic character, free fatty acids exported to the blood plasma are transported by albumin toward the muscle and liver tissues. Uptake of fatty acids into the liver or muscle cells is carried out by Fatty Acid Binding Protein (FABP), Fatty Acid Transporter Protein (FATP), and Fatty Acid Transporter (FAT-CD36) (Figure 1). Intracellular fatty acids are then activated in the form of acyl-CoA in hepatocytes and muscle cells and subsequently translocated into the mitochondrial matrix by the fatty acid transporter CAT1 and degraded by β-oxidation (Figure 1).

Acetyl-CoA overproduction by β-oxidation of fatty acids causes the allosteric inhibition of the pyruvate dehydrogenase complex (Figure 1). This allows the production of OAA from pyruvate, and thus the beginning of hepatic gluconeogenesis (Figure 1) (Fuchs et al., 2012; Sánchez-Gurmaches et al., 2018). Glycerol obtained from TAG degradation is incorporated at the level of DHAP, feeding the gluconeogenesis in the liver (Figure 1). Glycerol is the most efficient gluconeogenic substrate, compared to alanine, lactate, and other carbon skeletons of some gluconeogenic amino acids (Figure 1). In energy terms, the synthesis of one molecule of glucose from glycerol requires two ATP molecules, instead of six ATP equivalents if gluconeogenesis begins from pyruvate (Fry & Carter, 2019; Pietrocola et al., 2017).

Hepatic metabolism of fructose

Fructose, obtained from fruits and honey, is an intense-flavor sweetener that is added to most processed foods (Bray, 2013; Feinman & Fine, 2013). Fructose presentations include free fructose, sucrose, polysaccharides (fructans) in syrups and nectars, among others (Choo et al., 2018). The rise in fructose consumption has been associated with the increase in obesity and the onset of the metabolic syndrome (Elliott, Keim, Stern, Teff & Havel, 2002; Sievenpiper et al., 2014) (Figure 2). This type of sugar is metabolized largely by hepatocytes, and its assimilation takes place in parallel with the catabolism of other hexoses in glycolysis (Ter Horst & Serlie, 2017). Glut 2 mediates the transport of fructose into the hepatocytes, and the monosaccharide is phosphorylated by fructokinase C, also known as ketohexokinase. Glyceraldehyde and DHAP are produced from fructose 1-phosphate by aldolase B, which allows the integration of fructose into the middle part of glycolysis (Figure 2).

Fructose is a highly lipogenic sugar in comparison with other monosaccharides (Loza-Medrano et al., 2019; Mai & Yan, 2019), because it enters the glycolytic pathway without any allosteric or hormonal control of the fructokinase C. For instance, hexokinases and PFK-1 prevent an accelerated rate of ATP consumption and avoid the overproduction of ADP and trioses that feed lipogenesis (Abdelmalek et al., 2012; Mock, Lateef, Benedito & Tou, 2017).

The increase in the formation of DHAP derived from fructose metabolism, augments the synthesis of fatty acids and the accumulation of triacylglycerol deposits that can progress to steatosis (Figure 2), along with an increase in VLDL and a decrease in High-Density Lipoproteins (HDL) (Ishimoto et al., 2013; Roglans et al., 2007).

At the molecular level, frequent fructose intake increases the production of mRNAs for FAS and the stearoyl-CoA desaturase 1 (SCD1), which stimulates the synthesis of triacylglycerols and the introduction of the first double bond to the saturated fatty acids, respectively (Basaranoglu, Basaranoglu, Sabuncu & Senturk, 2013). In addition, fructose increases the mRNA of the Carbohydrate-Responsive Element-Binding Proteins (ChREBP) and the mRNA of proteins that participate in the STAT3 pathway involved in the release of leptin (Roglans et al., 2007). It has been stated that ChREBP is a transcription factor that regulates the synthesis of enzymes participating in glycolysis, fructolysis and gluconeogenesis. Also, ChREBP is involved in the de novo synthesis of triacylglycerols and cholesterol, regardless of insulin activation (Ter Horst & Serlie, 2017).

Frequent fructose intake is associated with hypertension, insulin resistance, steatosis and hypertriglyceridemia, and causes non-alcoholic fatty liver disease in people with obesity, in which the nuclear receptor PPARαɣ and its target NF-κβ participate in the decrease of the rate of β- oxidation under gluconeogenesis conditions (Costa Gil & Spinedi, 2017; Laughlin et al., 2014; Roglans et al., 2002). High fructose intake is also related to the onset of gout disease (Figure 1). As a consequence of the increase in fructokinase C activity and the associated high rate of ATP consumption, there is a rise in the concentrations of ADP and AMP that causes a higher production of uric acid and inflammation of some joints (Mai & Yan, 2019). The link between fructose intake and gout arthritis has been observed in various animal models within minutes after the ingestion of fructose (Jensen et al., 2018).

In addition, the increase of uric acid levels results in the activation of cytosolic NADPH oxidase that translocates to the mitochondria, generating oxidative stress and the inhibition of the aconitase 2, and resulting in the accumulation of citrate in the mitochondrial matrix (Jamnik et al., 2016; Jensen et al., 2018). This causes the export of citrate to the cytoplasm and the stimulation of lipogenesis and cholesterogenesis (Figure 1). The oxidative stress in mitochondria spreads to the endoplasmic reticulum, activating the Sterol Regulatory Element-Binding transcription factor 1 (SREBP-1), which in turn increases the transcript levels of genes involved in lipogenesis and cholesterol synthesis (Jensen et al., 2018; Lustig, 2010; Samuel, 2011) (Figure 1).

Control of Randle cycle by mTORC1 and AMPK

The mammalian target of rapamycin (mTOR) is a kinase that forms two complexes in mammals: mTORC1 and mTORC2. mTORC1 is activated by amino acids (Chen, Wei, Liu & Guan, 2014; Cheng & Saltiel, 2006), growth factors and hormones, such as insulin (Baena et al., 2015; Verges, 2018). mTORC2 is also regulated by growth factors and is involved in cytoskeleton remodeling and sphingolipid synthesis (Figure 3). During the postprandial state, insulin stimulates phosphoinositide-dependent kinase 1 (PDK1), which leads to the activation of PKB/Akt signaling pathway, inhibition of the TSC1/TSC2 complex (tuberous sclerosis complex 1 and 2), and activation of mTORC1, which promotes lipogenesis, glycolysis, and glycogen synthesis (Asati, Mahapatra & Bharti, 2016; Jiang et al., 2008; Kumar et al., 2010; Naito, Kuma & Mizushima, 2013; Verges, 2018). On the contrary, the AMP-dependent Kinase (AMPK) is hormonally downregulated under the hyperglycemia status and activated during fasting or exercise conditions. Activation of the AMPK depends on the stimulation of both the AMPc-dependent protein kinase (PKA) and the human tumor suppressor liver kinase 1 (LKB1), and the increase in the concentration of AMP (Kim & He, 2013). Along with the stimulation of PKA and AMPK there is a decrease in the main lipogenic pathways, such as fatty acid synthesis, triacylglycerol accumulation and cholesterogenesis, and activation of gluconeogenesis (Hasenour et al., 2017), glycogen degradation, lipolysis and mitochondrial β-oxidation, thereby increasing ketogenesis in the liver (Cardaci, Filomeni, & Ciriolo, 2012). AMPK, through the phosphorylation of ACC and HMG-CoA reductase, inhibits the synthesis of fatty acids and cholesterol, respectively.

In short, triacylglycerol accumulation in white fat deposits, liver tissue, and between fiber bundles is caused by hypercaloric diets rich in fast-digesting carbohydrates, along with the sedentary lifestyle habits of Western societies (Perera & Turner, 2016). Hypertriglyceridemia and hypercholesterolemia are involved in the pathophysiology of health problems, such as high blood pressure, diabetes mellitus 2, atherosclerosis and obesity, among other diseases (Ke, Xu, Li, Luo & Huang, 2018; Nakamura et al., 2014; Palomer et al., 2013; Possik et al., 2017).

Conclusions

There is a metabolic relationship between sugar consumption and fat accumulation. In the specific case of fructose, the excessive consumption of this sugar causes depletion of cellular ATP, steatosis, obesity, metabolic syndrome, and an increase in the production of uric acid. These adverse metabolic effects are the consequence of the lack of regulatory mechanisms for the incorporation of fructose into the glycolytic pathway. A new addition to the Randle cycle is the incorporation of mTORC1 and the antagonistic effect of the AMPK to ensure an efficient regulation of lipogenesis and lipolysis, respectively. In terms of public policy, authorities of health institutes should advise against the abuse of carbohydrate consumption.

Acknowledgments

This work was supported by the Universidad Nacional Autónoma de México (UNAM), Programa de Apoyo a Proyectos de Investigación Tecnológica [PAPIIT IN222117]; Consejo Nacional de Ciencia y Tecnología, CONACYT [254904-JPP] and [256520-GGS]. Instituto Politécnico Nacional- Secretaría de Investigación y Posgrado, [IPN-SIP 20190200]. We are grateful to Oscar Iván Luqueño Bocardo for the design of Figure 1.

References

Abdelmalek, M. F, Lazo, M., Horska, A., Bonekamp, S., Lipkin, E. W., Balasubramanyam, A., Bantle, J. P., Johnson, R. J., Diehl, A. M. & Clark, J. M. Fatty Liver Subgroup of Look AHEAD Research Group. (2012). Higher dietary fructose is associated with impaired hepatic adenosine triphosphate homeostasis in obese individuals with type 2 diabetes. Hepatology, 56(3), 952-960. DOI: 10.1002/hep.25741

Aguilar, L. R. , Pardo, J. P., Lomelí, M. M., Bocardo, O. I. L., Juárez Oropeza, M. A. & Guerra Sánchez, G. (2017). Lipid droplets accumulation and other biochemical changes induced in the fungal pathogen Ustilago maydis under nitrogen-starvation. Arch. Microbiol., 199(8):1195-1209. DOI: 10.1007/s00203-017-1388-8

Ameer, F., Scandiuzzi, L., Hasnain, S., Kalbacher, H. & Zaidi, N. (2014). De novo lipogenesis in health and disease. Metabolism, 63 (7), 895-902. DOI: 10.1016/j.metabol.2014.04.003

Asati, V., Mahapatra, D. K. & Bharti, S. K. (2016). PI3K/Akt/mTOR and Ras/Raf/MEK/ERK signaling pathways inhibitors as anticancer agents: Structural and pharmacological perspectives. Eur. J.Med. Chem., 109, 314-341. DOI: 10.1016/j.ejmech.2016.01.012

Baena, M., Sanguesa, G., Hutter, N., Sánchez, R. M., Roglans, N., Laguna, J. C. & Alegret, M. (2015). Fructose supplementation impairs rat liver autophagy through mTORC activation without inducing endoplasmic reticulum stress. Biochim. Biophys. Acta, 1851(2), 107-116. DOI: 10.1016/j.bbalip.2014.11.003

Barbosa, A. D. & Siniossoglou, S. (2017). Function of lipid droplet-organelle interactions in lipid homeostasis. Biochim. Biophys. Acta Mol. Cell Res., 1864(9), 1459-1468. DOI: 10.1016/j.bbamcr.2017.04.001

Bartelt, A., Weigelt, C., Cherradi, M. L., Niemeier, A., Todter, K., Heeren, J. & Scheja, L. (2013). Effects of adipocyte lipoprotein lipase on de novo lipogenesis and white adipose tissue browning. Biochim Biophys Acta, 1831(5), 934-942. DOI: 10.1016/j.bbalip.2012.11.011

Basaranoglu, M., Basaranoglu, G., Sabuncu, T. & Senturk, H. (2013). Fructose as a key player in the development of fatty liver disease. World J. Gastroenterol., 19(8), 1166-1172. DOI: 10.3748/wjg.v19.i8.1166

Bray, G. A. (2013). Energy and fructose from beverages sweetened with sugar or high-fructose corn syrup pose a health risk for some people. Adv. Nutr., 4(2), 220-225. DOI: 10.3945/an.112.002816

Cardaci, S., Filomeni, G. & Ciriolo, M. R. (2012). Redox implications of AMPK-mediated signal transduction beyond energetic clues. J. Cell Sci., 125(Pt 9), 2115-2125. DOI: 10.1242/jcs.095216

Chen, Y., Wei, H., Liu, F. & Guan, J. L. (2014). Hyperactivation of mammalian target of rapamycin complex 1 (mTORC1) promotes breast cancer progression through enhancing glucose starvation-induced autophagy and Akt signaling. J. Biol. Chem., 289(2), 1164-1173. DOI: 10.1074/jbc.M113.526335

Cheng, A. & Saltiel, A. R. (2006). More TORC for the gluconeogenic engine. Bioessays, 28(3), 231-234. DOI: 10.1002/bies.20375

Choo, V. L., Viguiliouk, E., Blanco Mejia, S., Cozma, A. I., Khan, T.A., Ha, V., Wolever, T. M. S., Leiter, L. A., Vuksan, V., Kendall, C. W. C., de Souza, R. J., Jenkins, D. J. A. & Sievenpiper, J. L. (2018). Food sources of fructose-containing sugars and glycaemic control: systematic review and meta-analysis of controlled intervention studies. BMJ, 363, k4644. DOI: 10.1136/bmj.k4644

Costa Gil, J. E. & Spinedi, E. (2017). La tormentosa relación entre las grasas y el desarrollo de la diabetes mellitus de tipo 2: actualizado. Parte I. Revista Argentina de Endocrinología y Metabolismo, 54, 109-123. DOI: 10.1016/j.raem.2017.06.001

Elliott, S. S., Keim, N. L., Stern, J. S., Teff, K. & Havel, P. J. (2002). Fructose, weight gain, and the insulin resistance syndrome. Am. J. Clin. Nutr., 76(5), 911-922. DOI: 10.1093/ajcn/76.5.911

Feinman, R. D. & Fine, E. J. (2013). Fructose in perspective. Nutr. Metab. (Lond.), 10(1), 45. DOI: 10.1186/1743-7075-10-45

Fry, B. & Carter, J. F. (2019). Stable carbon isotope diagnostics of mammalian metabolism, a high-resolution isotomics approach using amino acid carboxyl groups. PLoS One, 14(10), e0224297. DOI: 10.1371/journal.pone.0224297

Fuchs, C. D., Claudel, T., Kumari, P., Haemmerle, G., Pollheimer, M. J., Stojakovic, T., Scharnagl, H., Halilbasic, E., Gumhold, J., Silbert, D., Koefeler, H. & Trauner, M. (2012). Absence of adipose triglyceride lipase protects from hepatic endoplasmic reticulum stress in mice. Hepatology, 56(1), 270-280. DOI: 10.1002/hep.25601

Gómez Candela, C. & Palma Milla, S. (2013). Una visión global, actualizada y crítica del papel del azúcar en nuestra alimentación. Nutrición Hospitalaria, 28, 1-4.

Hasenour, C. M., Ridley, D. E., James, F. D., Hughey, C. C., Donahue, E. P., Viollet, B., Foretz, M., Young, J. D. & Wasserman, D. H. (2017). Liver AMP-Activated Protein Kinase Is Unnecessary for Gluconeogenesis but Protects Energy State during Nutrient Deprivation. PLoS One, 12(1), e0170382. DOI: 10.1371/journal.pone.0170382

Hilton, C., Karpe, F. & Pinnick, K. E. (2015). Role of developmental transcription factors in white, brown and beige adipose tissues. Biochim. Biophys. Acta, 1851(5), 686-696. DOI: 10.1016/j.bbalip.2015.02.003

Hruby, A. & Hu, F. B. (2015). The Epidemiology of Obesity: A Big Picture. Pharmacoeconomics, 33(7), 673-689. DOI: 10.1007/s40273-014-0243-x

Ishimoto, T., Lanaspa, M. A., Rivard, C. J., Roncal-Jimenez, C. A., Orlicky, D. J., Cicerchi, C., McMahan, R. H., Abdelmalek, M. F., Rosen, H. R., Jackman, M. R., MacLean, P. S., Diggle, C. P., Asipu, A., Inaba, S., Kosugi, T., Sato, W., Maruyama, S., Sánchez-Lozada, L. G., Sautin, Y.Y ., Hill, J. O., Bonthron, D. T. & Johnson, R. J. (2013). High-fat and high-sucrose (western) diet induces steatohepatitis that is dependent on fructokinase. Hepatology, 58(5), 1632-1643. DOI: 10.1002/hep.26594

Jamnik, J., Rehman, S., Blanco Mejia, S., de Souza, R. J, Khan, T. A., Leiter, L. A., Wolever, T. M., Kendall, C. W., Jenkins, D. J. & Sievenpiper, J. L. (2016). Fructose intake and risk of gout and hyperuricemia: a systematic review and meta-analysis of prospective cohort studies. BMJ Open, 6(10), e013191. DOI: 10.1136/bmjopen-2016-013191

Jensen, T., Abdelmalek, M. F., Sullivan, S., Nadeau, K. J., Green, M., Roncal, C., Nakagawa, T., Kuwabara, M., Sato, Y., Kang, D. H., Tolan, D. R., Sanchez-Lozada, L. G., Rosen, H. R, Lanaspa, M. A., Diehl, A. M. & Johnson, R. J. (2018). Fructose and sugar: A major mediator of non-alcoholic fatty liver disease. J. Hepatol., 68(5), 1063-1075. DOI: 10.1016/j.jhep.2018.01.019

Jiang, X., Kenerson, H., Aicher, L., Miyaoka, R., Eary, J., Bissler, J. & Yeung, R. S. (2008). The tuberous sclerosis complex regulates trafficking of glucose transporters and glucose uptake. Am. J. Pathol., 172(6), 1748-1756. DOI: 10.2353/ajpath.2008.070958

Ke, R., Xu, Q., Li, C., Luo, L. & Huang, D. (2018). Mechanisms of AMPK in the maintenance of ATP balance during energy metabolism. Cell Biol. In.. 42(4), 384-392. DOI: 10.1002/cbin.10915

Kim, I. & He, Y. Y. (2013). Targeting the AMP-Activated Protein Kinase for Cancer Prevention and Therapy. Front. Oncol., 3, 175. DOI: 10.3389/fonc.2013.00175

Kory, N., Farese, R. V., Jr. & Walther, T. C. (2016). Targeting Fat: Mechanisms of Protein Localization to Lipid Droplets. Trends Cell Biol., 26(7), 535-546. DOI: 10.1016/j.tcb.2016.02.007

Kumar, A., Lawrence, J. C. Jr. , Jung, D.Y., Ko, H. J., Keller, S. R., Kim, J. K., Magnuson, M. A. & Harris, T. E. (2010). Fat cell-specific ablation of rictor in mice impairs insulin-regulated fat cell and whole-body glucose and lipid metabolism. Diabetes, 59(6), 1397-1406. DOI: 10.2337/db09-1061

Laughlin, M. R., Bantle, J. P., Havel, P. J., Parks, E., Klurfeld, D. M., Teff, K. & Maruvada, P. (2014). Clinical research strategies for fructose metabolism. Adv. Nutr., 5(3), 248-259. DOI: 10.3945/an.113.005249

Loza-Medrano, S. S., Baiza-Gutman, L. A., Manuel-Apolinar, L., García-Macedo, R., Damasio-Santana, L., Martínez-Mar, O. A., Sánchez-Becerra, M. C., Cruz-López, M., Ibáñez-Hernández, M. A. & Díaz-Flores, M. (2019). High fructose-containing drinking water-induced steatohepatitis in rats is prevented by the nicotinamide-mediated modulation of redox homeostasis and NADPH-producing enzymes. Mol. Biol. Rep., 47(1), 337-351. DOI: 10.1007/s11033-019-05136-4

Lustig, R. H. (2010). Fructose: metabolic, hedonic, and societal parallels with ethanol. J. Am. Diet. Assoc., 110(9), 1307-1321. DOI: 10.1016/j.jada.2010.06.008

Mai, B. H. & Yan, L. J. (2019). The negative and detrimental effects of high fructose on the liver, with special reference to metabolic disorders. Diabetes Metab. Syndr. Obes., 12, 821-826. DOI: 10.2147/DMSO.S198968

Marcelino, H., Veyrat-Durebex, C., Summermatter, S., Sarafian, D., Miles-Chan, J., Arsenijevic, D., Zani, F., Montani, J. P., Seydoux, J., Solinas, G., Rohner-Jeanrenaud, F. & Dulloo, A. G. (2013). A role for adipose tissue de novo lipogenesis in glucose homeostasis during catch-up growth: a Randle cycle favoring fat storage. Diabetes, 62(2), 362-372. DOI: 10.2337/db12-0255

Mock, K., Lateef, S., Benedito, V. A. & Tou, J. C. (2017). High-fructose corn syrup-55 consumption alters hepatic lipid metabolism and promotes triglyceride accumulation. J. Nutr. Biochem., 39, 32-39. DOI: 10.1016/j.jnutbio.2016.09.010

Moran, T. H. & Ladenheim, E. E. (2016). Physiologic and Neural Controls of Eating. Gastroenterol. Clin. North. Am., 45(4), 581-599. DOI: 10.1016/j.gtc.2016.07.009

Mottillo, E. P., Balasubramanian, P., Lee, Y. H., Weng, C., Kershaw, E. E. & Granneman, J. G. (2014). Coupling of lipolysis and de novo lipogenesis in brown, beige, and white adipose tissues during chronic beta3-adrenergic receptor activation. J. Lipid. Res., 55(11), 2276-2286. DOI: 10.1194/jlr.M050005

Murray, R. D. (2019). 100% Fruit Juice in Child and Adolescent Dietary Patterns. J. Am. Coll. Nutr., 39(2), 122-127. DOI: 10.1080/07315724.2019.1615013

Naito, T., Kuma, A. & Mizushima, N. (2013). Differential contribution of insulin and amino acids to the mTORC1-autophagy pathway in the liver and muscle. J. Biol. Chem., 288(29), 21074-21081. DOI: 10.1074/jbc.M113.456228

Nakamura, M. T., Yudell, B. E. & Loor, J. J. (2014). Regulation of energy metabolism by long-chain fatty acids. Prog. Lipid. Res., 53, 124-144. DOI: 10.1016/j.plipres.2013.12.001

Nelson, D. L. & Cox, M. (2017). Lehninger principles of biochemistry. W.H. Freeman. New York.

Ogden, C. L., Yanovski, S. Z., Carroll, M. D. & Flegal, K. M. (2007). The epidemiology of obesity. Gastroenterology, 132(6), 2087-2102. DOI: 10.1053/j.gastro.2007.03.052

Palomer, X., Salvado, L., Barroso, E. & Vazquez-Carrera, M. (2013). An overview of the crosstalk between inflammatory processes and metabolic dysregulation during diabetic cardiomyopathy. Int. J. Cardiol., 168(4), 3160-3172. DOI: 10.1016/j.ijcard.2013.07.150

Pearlman, M., Obert, J. & Casey, L. (2017). The Association Between Artificial Sweeteners and Obesity. Curr. Gastroenterol. Rep., 19(12), 64. DOI: 10.1007/s11894-017-0602-9

Pereira, M. J., Thombare, K., Sarsenbayeva, A., Kamble, P. G., Almby, K., Lundqvist, M. & Eriksson, J. W. (2020). Direct effects of glucagon on glucose uptake and lipolysis in human adipocytes. Mol. Cell Endocrinol., 503, 110696. DOI: 10.1016/j.mce.2019.110696

Perera, N. D. & Turner, B. J. (2016). AMPK Signalling and Defective Energy Metabolism in Amyotrophic Lateral Sclerosis. Neurochemical Research, 41(3), 544-553. DOI: 10.1007/s11064-015-1665-3

Pietrocola, F., Demont, Y., Castoldi, F., Enot, D., Durand, S., Semeraro, M., Baracco, E. E., Pol, J., Bravo-San Pedro, J. M., Bordenave, C., Levesque, S., Humeau, J., Chery, A., Métivier, D., Madeo, F., Maiuri, M. C. & Kroemer, G. (2017). Metabolic effects of fasting on human and mouse blood in vivo. Autophagy, 13(3), 567-578. DOI: 10.1080/15548627.2016.1271513

Possik, E., Madiraju, S. R. M. & Prentki, M. (2017). Glycerol-3-phosphate phosphatase/PGP: Role in intermediary metabolism and target for cardiometabolic diseases. Biochimie, 143, 18-28. DOI: 10.1016/j.biochi.2017.08.001

Priyadarshini, E. & Anuradha, C. V. (2017). Glucocorticoid Antagonism Reduces Insulin Resistance and Associated Lipid Abnormalities in High-Fructose-Fed Mice. Can. J. Diabetes, 41(1), 41-51. DOI: 10.1016/j.jcjd.2016.06.003

Quiroga, A. D. & Lehner, R. (2012). Liver triacylglycerol lipases. Biochim. Biophys. Acta, 1821(5), 762-769. DOI:10.1016/j.bbalip.2011.09.007

Quiroga, A. D. & Lehner, R. (2018). Pharmacological intervention of liver triacylglycerol lipolysis: The good, the bad and the ugly. Biochem. Pharmacol., 155, 233-241. DOI: 10.1016/j.bcp.2018.07.005

Rambold, A. S., Cohen, S. & Lippincott-Schwartz, J. (2015). Fatty acid trafficking in starved cells: regulation by lipid droplet lipolysis, autophagy, and mitochondrial fusion dynamics. Dev. Cell, 32(6), 678-692. DOI: 10.1016/j.devcel.2015.01.029

Randle, P. J., Garland, P. B., Hales, C. N. & Newsholme, E. A. (1963). The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet, 1(7285), 785-789. DOI: 10.1016/s0140-6736(63)91500-9

Rodríguez Delgado, J. (2017). Azúcares... ¿los malos de la dieta? Pediatría Atención Primaria, 19, 69-75.

Roglans, N., Sanguino, E., Peris, C., Alegret, M., Vázquez, M., Adzet, T., Díaz, C., Hernández, G., Laguna, J. C. & Sánchez, R. M. (2002). Atorvastatin treatment induced peroxisome proliferator-activated receptor alpha expression and decreased plasma nonesterified fatty acids and liver triglyceride in fructose-fed rats. J. Pharmacol. Exp. Ther., 302(1), 232-239. DOI: 10.1124/jpet.302.1.232

Roglans, N., Vila, L., Farre, M., Alegret, M., Sánchez, R. M., Vázquez-Carrera, M. & Laguna, J. C. (2007). Impairment of hepatic Stat-3 activation and reduction of PPARalpha activity in fructose-fed rats. Hepatology, 45(3), 778-788. DOI: 10.1002/hep.21499

Samuel, V. T. (2011). Fructose induced lipogenesis: from sugar to fat to insulin resistance. Trends Endocrinol. Metab., 22(2), 60-65. DOI: 10.1016/j.tem.2010.10.003

Sánchez-Gurmaches, J., Tang, Y., Jespersen, N. Z., Wallace, M., Martinez Calejman, C., Gujja, S., Li, H., Edwards, Y. J. K., Wolfrum, C., Metallo, C. M., Nielsen, S., Scheele, C. & Guertin, D. A. (2018). Brown Fat AKT2 Is a Cold-Induced Kinase that Stimulates ChREBP-Mediated De Novo Lipogenesis to Optimize Fuel Storage and Thermogenesis. Cell Metab., 27(1), 195-209 e196. DOI: 10.1016/j.cmet.2017.10.008

Sievenpiper, J. L., de Souza, R. J., Cozma, A. I., Chiavaroli, L., Ha, V. & Mirrahimi, A. (2014). Fructose vs. glucose and metabolism: do the metabolic differences matter? Curr. Opin. Lipidol., 25(1), 8-19. DOI: 10.1097/MOL.0000000000000042

Smith, K. B. & Smith, M. S. (2016). Obesity Statistics. Primare, 43(1), 121-135, ix. DOI: 10.1016/j.pop.2015.10.001

Song, Z., Xiaoli, A. M. & Yang, F. (2018). Regulation and Metabolic Significance of De Novo Lipogenesis in Adipose Tissues. Nutrients, 10(10). DOI: 10.3390/nu10101383

Stanhope, K. L. (2016). Sugar consumption, metabolic disease and obesity: The state of the controversy. Crit. Rev. Clin. Lab. Sci., 53(1), 52-67. DOI: 10.3109/10408363.2015.1084990

Summermatter, S., Marcelino, H., Arsenijevic, D., Buchala, A., Aprikian, O., Assimacopoulos-Jeannet, F., Seydoux, J., Montani, J. P., Solinas, G. & Dulloo, A. G. (2009). Adipose Tissue Plasticity During Catch-Up Fat Driven by Thrifty Metabolism Diabetes, 58(10), 2228-2237. DOI: 10.2337/db08-1793

Ter Horst, K. W. & Serlie, M. J. (2017). Fructose Consumption, Lipogenesis, and Non-Alcoholic Fatty Liver Disease. Nutrients, 9(9). DOI: 10.3390/nu9090981

Verges, B. (2018). mTOR and Cardiovascular Diseases: Diabetes Mellitus. Transplantation, 102(2S Suppl 1), S47-S49. DOI: 10.1097/TP.0000000000001722

Yoon, M-S. (2017). The Role of Mammalian Target of Rapamycin (mTOR) in Insulin Signaling. Nutrients 2017, 9, 1176. DOI:10.3390/nu9111176

World Health Organization. World Health Statistics (2018): Monitoring Health for the SDGs., 2018.

Author notes

^* E-mail: pardov@bq.unam.mx^** E-mail: genaromatus@bq.unam.mx^*** E-mail: lusromaguila@bq.unam.mx

Conflict of interest declaration