High salt intake causes leptin resistance and obesity in mice by stimulating endogenous fructose production and metabolism

Abstract

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.

Acute effects of salt on blood pressure are mediated by serum osmolality

“…Other potential mechanisms include effects on vasopressin or by stimulating endogenous cardiotonic steroids such as ouabain and marinobufagenin . High salt_induced osmolality may also stimulate the aldose reductase_fructokinase pathway in the hypothalamus that might mediate blood pressure responses . Thus, salt_induced hyperosmolarity may be involved in both classical renal and central nervous system blood pressure control mechanisms.…”

Fructose metabolism as a common evolutionary pathway of survival associated with climate change, food shortage and droughts

“…). In turn, aldose reductase can be stimulated by high glucose levels (such as in diabetes), by high‐salt diets (which increases osmolality, a known stimulant of aldose reductase), heat, tissue hypoxia, oxidative stress and by fructose and uric acid . In western societies, the main sources of fructose are from table sugar (sucrose) and the sweetener, high‐fructose corn syrup (HFCS).…”

“…A high serum osmolality, such as occur in dehydration or high‐salt intake, has been found to stimulate endogenous fructose pathway through the activation of aldose reductase. In this regard, blood pressure rise can be prevented in hyperosmolar animals lacking fructokinase . High‐salt intake also interacts with dietary fructose to raise blood pressure .…”

Impact factors that modulate gastric cancer risk in Helicobacter pylori‐infected rodent models

“…HSD could be an independent factor in promoting gastric carcinogenesis. Emerging studies have shown that HSD is associated with diseases other than GC, such as hypertension, obesity, diabetes, fatty liver, neurovascular, and cognition dysfunction . Furthermore, HSD is closely associated with an altered Th17 response in the disease process .…”

“…Emerging studies have shown that HSD is associated with diseases other than GC, such as hypertension, obesity, diabetes, fatty liver, neurovascular, and cognition dysfunction. [72][73][74] Furthermore, HSD is closely associated with an altered Th17 response in the disease process. 72,74,75 However, the precise mechanism through which HSD interacts with the host and bacteria to promote gastric carcinogenesis remains to be elucidated.…”