Fructose-induced inflammation and increased cortisol: A new mechanism for how sugar induces visceral adiposity☆
Section snippets
Visceral versus subcutaneous fat storage
Fat stored below the skin is known as subcutaneous fat and when it gets stored within the abdominal cavity, it is known as visceral adiposity. Visceral fat, also referred to as abdominal fat, is stored underneath the peritoneal cavity and is more active in secreting proinflammatory cytokines. Thus, storing visceral fat is more metabolically harmful as compared to subcutaneous fat (fat stored just beneath the skin). A protruding belly and large waistline is a clear indicator of visceral fat
Current dietary practices with regards to fructose
Sucrose (or table sugar) and high-fructose corn syrup (HFCS) are made up of both fructose and glucose with a ratio of 50:50 (for sucrose) and 55:42 (for HFCS), respectively. The overconsumption of these added sugars has been implicated in causing fatty liver and insulin resistance.32., 33. While it was previously thought that fructose may be more beneficial on glycemic control as it has a lower glycemic index,34., 35. it is now recognized that fructose has chronic deleterious effects on health
Absorption and metabolism of fructose
The process of fructose absorption is not entirely understood, but it is suggested that its absorption takes place at the jejunum via the GLUT-5 transporter. GLUT5 is also expressed in the membranes of adipocytes, kidney, muscle, and brain cells.38 After absorption, fructose is carried on to the liver where it is primarily metabolized.39
While glucose and fructose have similar structures, their metabolism is quite different.40 In contrast to glucose, the metabolism of fructose is not regulated
Fructose causing inflammation and insulin resistance in adipocytes and liver
The overconsumption of added fructose provokes metabolic changes that result in a chronic low-grade inflammation, insulin resistance and adiposity.44 Fructose over-consumption has tissue-specific effects on the regulation of metabolic inflammation. Several studies have shown that the overconsumption of fructose can lead to an increase in macrophage infiltration (via monocyte chemoattractant protein-1 [MCP-1] and intracellular adhesion molecule-1 [ICAM-1] induction) into adipocytes.45., 46., 47.
Glucocorticoids: background and roles in fructose-induced inflammation
Glucocorticoids (cortisol and cortisone are present in man while corticosterone and dehydrocorticosterone are present in rodents) are synthesized in and secreted from the zona fasciculata of the adrenal gland, under the regulation of adrenocorticotropic hormone (ACTH) which is secreted from the anterior pituitary gland. The secretion of ACTH is under the control of corticotropin-releasing hormone (CRH) and vasopressin which are secreted from the hypothalamus. This complex set of hormone
Fructose increases intracellular cortisol via 11β-HSD1
It is well-known fact that excess cortisol can also induce fat accumulation in the central part of the abdomen, facial, dorsocervical region (buffalo hump) and arterial walls.73., 74., 75., 76., 77. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) isoenzyme activates cortisol from cortisone in men and corticosterone from 11-dehydrocorticosterone in rodents. Cortisone and 11-dehydrocorticosterone are inactive corticosteroids which are activated by 11β-HSD-1 to their active forms.78., 79., 80.
11β-HSD1 regulation and its actions
The two main factors regulating the levels of 11B–HSD are the levels of H6PD in the lumen of endoplasmic reticulum and generation of pro inflammatory mediators like TNF-α and IL-1. Several functional studies suggested that H6PD activity within the lumen of the endoplasmic reticulum plays a critical role in regulating the oxo-reductase activity of 11β-HSD-1 by providing NADPH.70 The consumption of a fructose-rich diet enhances the production of H6PD in turn facilitating activity of 11β–HSD-1 in
Fructose in the brain stimulates the HPA-axis and cortisol secretion
GLUT5 transporters are present in the blood-brain barrier, which suggests that circulating fructose can enter the brain.38 Moreover the polyol pathway (which converts endogenous glucose to fructose) resides in the brain and hence fructose likely has physiological effects in the brain via endogenous fructogenesis from glucose.108 Fructose has also been found to stimulate the hypothalamus, which induces hepatic gluconeogenesis via corticosterone release from the adrenal gland.109 Fructose
Downregulated PEPCK induced increase in release of FFA from adipocytes
PEPCK enzyme is primarily involved in gluconeogenesis and regulation of lipid metabolism.110 Fructose-induced inflammation and increase in glucocorticoids can have an impact on PEPCK transcription. Increases in glucocorticoids leads to an increase PEPCK transcription in liver while PEPCK transcription decreases in adipocytes. Since PEPCK upregulation leads to adipocyte lipid storage and decrease in FFA release from the adipocytes, its downregulation can lead to a decrease in lipid storage in
Fructose and weight gain
A systematic review of systematic reviews indicated that 83.3% of studies without conflicts to the food industry find a positive association between sugar sweetened beverages and weight gain or obesity.113 A systematic review and meta-analyses of randomised controlled trials and cohort studies concluded that among free living people ad libitum intake of free sugars or sugar sweetened beverages is a determinant of body weight, which may be mediated by increased hunger and energy intake when more
Conclusion
No matter how sweet it is to taste, added fructose (from sucrose and high fructose corn syrup) should be avoided in the diet, whereas consuming fruit seems to provide health benefits. Due to fructose induced inflammation and the subsequent increase in intracellular cortisol, visceral adiposity ensues. Indeed, fatty acids are subsequently released from the adipocytes to the visceral organs including liver, pancreas, skeletal muscle, and heart which can disrupt metabolic processes and impair
Statement of conflict of interest
Dr. DiNicolantonio is the author of The Salt Fix and operates the website thesaltfix.com.
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Statement of Conflict of Interest: see page 7.