The role of dietary salt in metabolism and energy balance: Insights beyond cardiovascular disease

Abstract

Dietary salt (NaCl) is essential to an organism's survival. However, today's diets are dominated by excessive salt intake, which significantly impacts individual and population health. High salt intake is closely linked to cardiovascular disease (CVD), especially hypertension, through a number of well‐studied mechanisms. Emerging evidence indicates that salt overconsumption may also be associated with metabolic disorders. In this review, we first summarize recent updates on the mechanisms of salt‐induced CVD, the effects of salt reduction and the use of salt substitution as a therapy. Next, we focus on how high salt intake can impact metabolism and energy balance, describing the mechanisms through which this occurs, including leptin resistance, the overproduction of fructose and ghrelin, insulin resistance and altered hormonal factors. A further influence on metabolism worth noting is the reported role of salt in inducing thermogenesis and increasing body temperature, leading to an increase in energy expenditure. While this result could be viewed as a positive metabolic effect because it promotes a negative energy balance to combat obesity, caution must be taken with this frame of thinking given the deleterious consequences of chronic high salt intake on cardiovascular health. Nevertheless, this review highlights the importance of salt as a noncaloric nutrient in regulating whole‐body energy homeostasis. Through this review, we hope to provide a scientific framework for future studies to systematically address the metabolic impacts of dietary salt and salt replacement treatments. In addition, we hope to form a foundation for future clinical trials to explore how these salt‐induced metabolic changes impact obesity development and progression, and to elucidate the regulatory mechanisms that drive these changes, with the aim of developing novel therapeutics for obesity and CVD.

1. INTRODUCTION

Dietary salt (NaCl) provides the body with sodium, which is essential for cellular homeostasis and a variety of physiological functions. Sodium plays a pivotal role in maintaining extracellular fluid volume and osmolality, as well as in transmembrane transport, particularly by mediating membrane and action potentials via sodium/potassium exchange. ¹ It is well established that the quantity of salt required to maintain normal physiological homeostasis in adult humans is <1.25 g/d. ² However, in modern diets, daily salt intake far exceeds this amount. ³ For example, epidemiological studies demonstrate that the average daily sodium consumption of most people in the United States is >3.2 g (equivalent to >8 g salt, sodium × 2.5 = salt). ⁴ The general average intake of salt reached 10.06 g/d, ⁵ and in some populations it has reached approximately 15 to 25 g/d. ⁶ Ample evidence has shown that long‐term over‐consumption of salt is harmful to health, contributing to the development of cardiovascular disease (CVD), particularly hypertension. ⁷ , ⁸ As such, health organizations around the world have established dietary guidelines for daily salt intake. The Dietary Guidelines for Americans, 2020‐2025 recommend that daily sodium intake in healthy adults should not exceed 2.3 g (5.75 g salt). ⁹ The World Health Organization (WHO) aims to lower daily dietary salt intake to <5 g/d. ¹⁰ , ¹¹ , ¹² In addition to avoiding excess consumption, low‐salt diets have been encouraged for patients with CVD, particularly heart failure (HF). However, given that sodium ions are an essential noncaloric nutrient, there has been some controversy in the field concerning how large the reduction in salt intake should be. ¹¹ In light of the potential shortcomings of sodium restriction, salt replacement therapy has been proposed as an alternative treatment strategy; this has been tested in the population, ¹³ , ¹⁴ with encouraging results.

Emerging evidence suggests that dietary salt may also influence metabolism and energy balance, especially energy expenditure, via several mechanisms including increasing lipolysis and thermogenesis, and regulating levels of key hormones such as leptin, natriuretic peptides, and aldosterone. ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ Intriguingly, both high and low salt intake have been shown to be associated with metabolic dysfunction, leading to insulin resistance (IR), leptin resistance, obesity and metabolic syndrome. ¹⁹ , ²⁰ , ²¹ The seemingly contradictory findings of salt's effect on energy homeostasis could be attributable to different research designs and conditions in human and animal studies. ²⁰ , ²² , ²³ , ²⁴ , ²⁵ , ²⁶ Nevertheless, these studies highlight the potential role of salt in regulating energy homeostasis and glucose metabolism. In this review, we first describe salt intake in the context of cardiovascular health—by far the dominant area in the appraisal of salt‐related health outcomes—by describing the recent updates in the mechanisms behind salt‐induced CVD, especially hypertension and HF. We then summarize the current evidence evaluating the metabolic effects of dietary salt intake (Figure 1) and possible underlying molecular mechanisms of the posited effects.

FIGURE 1.

High salt intake leads to cardiovascular and metabolic changes. High salt intake leads to hypertension via water retention. This is mediated by a number of mechanisms including increased activation of the renin angiotensin system (RAS) and the sympathetic nervous system, endothelial dysfunction, reduced atrial natriuretic peptide (ANP) and B‐type natriuretic peptide (BNP), overactive channel proteins sodium‐hydrogen exchanger‐3 [NHE‐3] and epithelial sodium channel [ENaC]), gut microbiome disturbance, inflammation and neurohumoral factors. Hypertension exacerbates cardiovascular complications by affecting the heart itself. High salt intake also promotes the overproduction of fructose and ghrelin, leptin resistance and insulin resistance, and reduce the circulating levels of key hormones such as adiponectin and glucagon‐like peptide 1 (GLP‐1). This may promote food intake and increased white adipose tissue (WAT), leading to obesity. Metabolic disorders contribute to the development and progression of cardiovascular disease (CVD). At the other end of the spectrum, high salt intake stimulates brown adipose tissue (BAT) thermogenesis, increasing energy expenditure. CVD, cardiovascular disease; DBP, diastolic blood pressure; SBP, systolic blood pressure

2. EFFECT OF HIGH ‐ SALT INTAKE ON CVD

Cardiovascular disease is the leading cause of disability and mortality worldwide and is characterized by HF, stroke, ischaemic heart disease and peripheral arterial disease. ²⁷ In 2017, CVD resulted in approximately 17.8 million deaths globally. ²⁸ , ²⁹ High salt intake has been shown to affect cardiovascular health in a number of ways; hypertension and HF are the most common and significant consequences, with harmful downstream health effects. They can arise via a variety of mechanisms, including several recently reported novel mechanisms, which are shown in Table 1.

TABLE 1.

Some novel mechanisms underlying high‐salt‐intake‐induced hypertension

Disease	Salt‐induced mechanisms	Description of mechanisms	References
Hypertension	Reduced ANP/BNP production	Genetically reduced production of ANP in mice leads to hypertension. Common genetic variants at the NPPA‐NPPB locus are linked to lower circulating NP levels contributing to salt sensitive hypertension in humans	30, 31, 32, 33, 34, 35, 36, 37
	Overactive NHE‐3 channel	Increased activity of the NHE‐3 channel causes pathological levels of sodium in the body, which raises blood volume, and increases blood pressure	38, 39, 40, 41, 42
	Overactive ENaC channel	High‐salt intake increases oxidative stress in the kidneys, enhancing ENaC expression and activity at the apical membrane. This further increases sodium absorption to promote hypertension. High‐salt intake can precipitate in hypertension via ENaC‐mediated sodium entrance in the kidneys, brain and immune system	42, 43, 44, 45, 46, 47, 48, 49, 50
	Disturbance to gut microbiome	High salt intake can decrease the prevalence of beneficial gut microbes, including Lactobacillus murinus, resulting in increased Th‐17 cells. This causes an increase in serum IL‐17A, which leads to the development of hypertension	39, 51, 52, 53
	Enhanced systemic inflammation	High‐salt intake increases circulating levels of CRP, TNF‐ α, IL‐6, IL‐23 in hypertensive patients. There is a linear relationship between CRP level and urine sodium excretion	84, 85, 86, 87, 89
	Altered neurohormonal factors	Salt activates the release of key neurotransmitters such as vasopressin to increase BP. Hypothalamic ARC NPY mediates salt‐induced hypertension via modulating expression of vasopressin and BDNF in the hypothalamus	69, 93, 94

Abbreviations: ANP, atrial natriuretic peptide; ARC, arcuate nucleus; BDNF, brain‐derived neurotrophic factor; BNP, B‐type natriuretic peptide; BP, blood pressure; CRP, C‐reactive protein; ENaC, epithelial sodium channel; IL, interleukin; NHE‐3, sodium proton‐exchanger‐3; NP, natriuretic peptide; NPY, neuropeptide Y; Th‐17, T helper‐17; TNF‐α, tumour necrosis factor‐α.

2.1. Effect of high salt intake on hypertension

Hypertension is one of the most common chronic vascular diseases, affecting 1.39 billion adults globally as of 2010. ⁵⁴ Hypertension was traditionally defined as a persistent systolic blood pressure (SBP) ≥140 mm Hg and/or a diastolic blood pressure (DBP) ≥90 mm Hg. ⁵⁵ , ⁵⁶ In the 2017 American College of Cardiology (ACC)/American Heart Association (AHA) hypertension Clinical Practice Guidelines, ⁵⁷ the diagnostic criterion for hypertension has been reduced to ≥130/80 mm Hg with SBP/DBP ranges of 130 to 139/80 to 89 mm Hg defined as Stage 1 hypertension, and ≥140/90 mm Hg as Stage 2 hypertension. The purpose of this reduction was to promote earlier interventions to reduce CVD risks and prevent major adverse CVD outcomes. However, there has been some controversy concerning BP measurements, BP cut‐offs, the target BP values to strive for, the timing and intensity of antihypertensive treatment, and the benefits of lowering BP targets in different age groups and ethnicities. ⁵⁶ , ⁵⁸ , ⁵⁹ In view of this, some clinical practice guidelines (ie, the 2018 European Society of Cardiology/European Society of Hypertension, the 2019 National Institute of Health and Care Excellence [NICE], and the 2020 International Society of Hypertension guidelines) still use the 140/90 mm Hg cut‐off for hypertension diagnosis. ⁵⁶ Nevertheless, all the guidelines have substantial accordance in their recommendations. ⁶⁰ Hypertension can be classified as primary (essential) or secondary. ⁶¹ Primary hypertension is by far the most common type ⁶¹ and refers to high BP of unknown, idiopathic origin. Poorly controlled hypertension increases the risk of HF, heart attack, stroke, renal failure and even death. ⁶² , ⁶³ , ⁶⁴ , ⁶⁵ The development of hypertension is influenced by various genetic, environmental and dietary factors, involving complex neuronal and hormonal regulation. ³⁰ , ⁶⁶ , ⁶⁷ , ⁶⁸ , ⁶⁹ High salt intake is strongly associated with the development of hypertension. ⁵⁷ , ⁷⁰ In light of this, understanding the underlying mechanisms of salt‐induced hypertension is an important area in cardiovascular health. Multiple factors have been studied and established as playing important roles in salt‐induced hypertension, including increased activation of the renin‐angiotensin‐aldosterone system (RAAS), endothelial dysfunction, sympathetic nervous system (SNS) hyperactivity, impaired renal and intestinal ion transport, altered natriuretic peptides (NPs) and others. As salt‐induced hypertension has been reviewed in depth in previous reports, ⁷¹ , ⁷² , ⁷³ here we describe some updates regarding these mechanisms that mediate salt‐induced hypertension.

2.1.1. Reduced levels of NPs in salt‐induced hypertension

Cardiac NPs (ANP and BNP) are hormones secreted from cardiomyocytes in response to volume expansion. They have been increasingly recognized as essential regulators in salt homeostasis, BP and cardiac remodelling via their natriuretic, diuretic and hypotensive actions. ³¹ , ³³ , ³⁴ , ⁷⁴ , ⁷⁵ Genetically reduced production of ANP leads to hypertension after a sodium load in mice. ³³ A genome‐wide association study ³¹ , ³⁴ identified that human common genetic variants linked to lower circulating NP concentrations contribute to salt‐sensitive hypertension. These NPs bind to their receptors in the vasculature, kidneys and adrenal glands and lower BP and fluid volume via functionally antagonizing the RAAS and the SNS activities. ³⁵ , ³⁶ , ³⁷ Paradoxically, there is evidence from clinical studies revealing that elevated circulating BNP levels are also found in pathological conditions such as raised BP, renal dysfunction and congestive HF, ⁷⁶ and increased circulating levels of BNP and NT‐ProBNP are associated with HF severity. ⁷⁷ The mechanisms behind this seemingly paradoxical finding are unclear, but it was speculated that this may represent a compensatory response to HF. ⁷⁸ Thus, more investigations with larger sample sizes, diverse ethnic backgrounds and comorbidities in humans as well as experimental studies in animal models will shed more light on this inconsistency and the associated mechanisms underlying the cardioprotective effects of NPs.

2.1.2. Increased sodium uptake via ion channel overactivity

Overactivity of sodium‐hydrogen exchanger‐3 (NHE‐3) and epithelial sodium channel (ENaC) has been shown to cause pathological levels of sodium in body compartments and cells. NHE‐3 is essential for intestinal sodium absorption, which increases water retention, resulting in increased BP. ³⁸ NHE‐3‐null mice ³⁸ were found to have significantly improved cardiovascular health. ⁴⁰ Additionally, studies showed that inhibiting gut NHE‐3 in disease models reduced BP and increased sodium excretion, highlighting the importance of the proximal colon in BP regulation. ⁴¹ , ⁷⁹ In addition to NHE‐3, ENaC activity in the kidneys, brain and immune system is also associated with salt‐induced hypertension. ⁴² , ⁴⁵ The kidneys are the main regulators of sodium homeostasis, where the proximal convoluted tubules and straight tubules of the nephron are the main sites of sodium reabsorption (60%–70%), ⁴⁶ , ⁴⁷ and the distal nephron is the main site of hormone‐regulated sodium absorption. ENaCs are most prominent in the distal nephron, and they play critical roles in sodium absorption regulated by hormones such as aldosterone, vasopressin, angiotensin II and insulin. ⁴⁷ High salt intake has been found to increase oxidative stress in the kidneys, which enhances ENaC expression and activity at the apical membrane, further increasing sodium absorption. ⁴³ In addition, salt overload can lead to increased sodium concentration in cerebrospinal fluid via ENaCs located at the inner surface of the endothelial membrane of brain capillaries, resulting in raised BP in rats. ⁴⁴ An immune‐mediated mechanism of salt‐induced hypertension is also seen via ENaC‐mediated dendritic cell activation, resulting in the formation of isolevuglandin–protein adducts in dendritic cells that triggered an autoimmune‐like reaction and increased the release of proinflammatory cytokines. ⁴⁸ , ⁴⁹ , ⁵⁰ This causes disrupted vascular function and hypertension.

2.1.3. Disturbance to the gut microbiome as a novel mechanism

Accumulating evidence suggests that the gut microbiome is an important environmental factor contributing to the development and progression of hypertension. ⁸⁰ Salt has been observed to cause an increase in Corynebacteriaceae species and a decrease in Lactobacillus species in the gut microbiome. ⁵¹ Such alteration has been reported to be responsible for causing CVD ⁸¹ and intestinal inflammation. ⁸² Elsewhere, Verhaar et al demonstrated that salt administration decreased the prevalence of Lactobacillus murinus in a rat model, resulting in increased proinflammatory splenic T helper (Th)‐17 cells. ⁵² In another study, Th‐17 cells were found to contribute to the development of hypertension via an increase in serum interleukin (IL)‐17A. ⁵³ The array of additional microbes and hormones that contribute to the development of hypertension has been summarized by Marques et al. ³⁹ Overall, such findings suggest that high salt intake can lead to hypertension, not only through increased sodium‐induced water retention but also by a novel mechanism of altered gut microbial environments. This is a research field with enormous potential that requires extensive investigation. To facilitate better study design and analysis, a guideline on gut microbiome studies in essential hypertension has been developed. ⁸³

2.1.4. Enhanced inflammatory responses to high salt intake

Dietary salt intake is associated with increased systemic inflammation in CVD, including hypertension. ⁷⁵ , ⁷⁶ Clinical studies have shown that hypertensive patients had elevated circulating levels of several inflammatory markers, including C‐reactive protein (CRP), tumour necrosis factor (TNF)‐α, IL‐6, IL‐23, procalcitonin and pentraxin‐3, ⁸⁶ , ⁸⁷ and lower levels of IL‐10, an anti‐inflammatory cytokine. ⁸⁸ For example, a randomized controlled trial (RCT) in 224 hypertensive patients reported that CRP was significantly higher in the high‐salt‐intake group compared with the medium‐ and low‐salt‐intake groups. ⁸⁵ This is in agreement with an early study involving 1597 participants that reported a linear relationship between CRP and urine sodium excretion (a proxy measurement that correlates well with dietary sodium intake) ⁸⁹ ; with a 100‐mM increase in sodium excretion, serum CRP increased by 1.20 mg/L. Likewise, patients with HF also had systemic activation of inflammatory responses, which was characterized by elevated circulating levels of TNF‐α, IL‐1β, IL‐6, and chemokines including MCP1 and IL‐8. ⁹⁰ , ⁹¹ More importantly, this systemic inflammation is closely correlated with HF severity. ⁹²

2.1.5. Altered neurohormonal factors

Recent studies have reported critical roles of the hypothalamus in the brain in controlling salt‐induced hypertension. ⁶⁹ , ⁹³ Salt activates the release of key neurotransmitters in the hypothalamus such as vasopressin to increase BP. ⁹³ Subsequently, hypothalamic arcuate nucleus neuropeptide Y (NPY), a critical regulator of energy balance ⁹⁴ was found to mediate salt‐induced hypertension via modulating vasopressin expression in the hypothalamic paraventricular nucleus. ⁶⁹ Moreover, arcuate nucleus NPY was previously shown to reduce brown adipose tissue thermogenesis and energy expenditure by suppressing the output of the SNS, ⁹⁵ a key system closely linked with salt‐induced hypertension. Together, these studies highlight the role of arcuate nucleus NPY in regulating both energy homeostasis and fluid homeostasis, the mechanisms of which warrant further investigation.

2.2. Salt reduction: For better or for worse?

Given the deleterious effects of salt intake on CVD, salt reduction has been suggested to reduce the risk of hypertension and cardiovascular events. ⁹⁶ , ⁹⁷ Previous studies have reported that reductions in dietary salt can protect against salt‐associated diseases, lowering BP and decreasing the risk of CVD. ¹⁰ , ⁹⁸ , ⁹⁹ In a 4‐month RCT among healthy families, individuals receiving salt‐reduced bread had beneficial changes in cardiovascular risk factors. ¹⁰⁰ Additionally, low‐salt diets can significantly reduce SBP in patients with isolated systolic hypertension. ¹⁰¹ In light of such findings, in another RCT, the Dietary Approaches to Stop Hypertension (DASH) diet, rich in whole grains, poultry, fish and nuts but lower in sodium, ¹⁰² was used for 30 days, and participants were found to have reduced BP. ¹⁰² In a prospective observational study involving 36 019 participants, the DASH diet was associated with a lower incidence of HF and reduced HF hospitalization. ¹⁰³ Therefore, all HF clinical practice guidelines recommend sodium restriction for patients with HF, ¹⁰⁴ , ¹⁰⁵ including the 2022 ACC/AHA heart failure guidelines. ¹⁰⁶ The beneficial effects of sodium restriction on HF are thought to be achieved by reducing SBP and DBP, oxidative stress, arterial stiffness, inflammation, and aldosterone levels. ¹⁰⁷

Despite the CVD benefits associated with sodium restriction, salt reduction interventions have also been observed to cause contrasting, paradoxical effects on cardiovascular health. In a recent open‐label RCT (the SODIUM‐HF study) in patients with HF recruited from six countries across the globe, the authors reported sodium restriction resulted in minimal effects on future adverse cardiovascular events. ¹⁰⁸ Previous evidence has shown that salt deficiency elevated low‐density lipoprotein, cholesterol, and triglyceride levels. ¹⁰⁹ A recent observational study analysed data from the HART study and demonstrated that sodium restriction (<2.5 g/d) in patients with HF was associated with an increased risk of death or hospitalization compared to those without a sodium‐restricted diet. ¹¹⁰ Likewise, low sodium intake showed worsened systemic inflammation in HF patients. ⁹¹ Moreover, studies showed that sodium restriction can cause inadequacies in macronutrients and micronutrients that could be associated with clinical instability. ¹¹¹ , ¹¹² Therefore, due to inconsistent evidence, there has been some debate about the clinical benefits or harm of sodium/salt restriction in HF patients. ¹¹³ , ¹¹⁴ , ¹¹⁵ , ¹¹⁶ , ¹¹⁷ , ¹¹⁸ , ¹¹⁹ , ¹²⁰ As such, more randomized clinical trials with larger sample sizes and sufficient racial and ethnic diversity are needed to definitively address the role of sodium restriction in HF management. Finally, it is important to note that effective salt reduction is very difficult to achieve at the individual level.

2.3. Salt substitution as a novel therapy

In light of the controversy related to extreme salt reduction, the substitution of dietary salt has been proposed as a promising regimen to improve cardiovascular health. Salt substitution refers to replacing part of one's dietary NaCl with potassium chloride (KCl), thus increasing potassium intake to reduce sodium intake. ¹³ It has been reported that high sodium and low potassium intake are associated with higher cardiovascular risk in a dose‐dependent manner. ¹²¹ Accordingly, recent studies found that reducing dietary sodium and increasing dietary potassium lowers BP. ¹²² , ¹²³ In a study of 20 995 participants with a history of stroke or hypertension, dietary salt substitution (75% NaCl, 25% KCl by mass) was associated with lower rates of major cardiovascular events and death compared with a regular salt diet (100% NaCl). ¹⁴ , ¹²⁴ In an RCT in rural India, hypertensive patients received salt substitution (70% NaCl and 30% KCl blend) for 1 to 3 months. Those in the salt substitution group had a substantial reduction in SBP compared with the regular salt group. ¹²⁵ Furthermore, a meta‐analysis supported the role of salt substitution as a therapy to reduce SBP and DBP for patients with Stage 2 hypertension. ¹²⁶ Importantly, a recent study measuring multiple 24‐hour urine samples suggested that diets with different ratios of sodium salt to potassium salt contributed differentially to cardiovascular outcomes. ¹²¹ The underlying mechanisms of salt substitution are yet to be revealed. One of the biggest questions is whether the beneficial effect comes from reduced sodium intake or increased potassium intake. It has been reported that individuals with a higher risk of cardiometabolic disease may benefit from increasing potassium intake. ¹²⁷ However, it is also well established that high potassium intake can lead to hyperkalaemia, which is linked with fatal cardiac complications. ¹²⁸ Therefore, future studies should aim to find optimal electrolyte blends for salt substitution regimens, which would involve designing experiments to test salt treatments with different sodium and potassium ratios. Such treatments could also be relevant to conditions outside of CVD, such as obesity.

3. THE EFFECT OF SALT INTAKE ON METABOLISM AND OBESITY

Obesity is a major global health problem. The prevalence of obesity continues to rise in adults and children, where 650 million individuals were obese worldwide in 2016 (WHO), with a total of 1.9 billion adults classified as overweight. Obesity is a strong risk factor for a myriad of health conditions such as diabetes, hypertension, stroke, COVID‐19 infection, cancer, and others. ²⁵ , ¹²⁹ , ¹³⁰ , ¹³¹ , ¹³² , ¹³³ , ¹³⁴ Effective treatments are urgently needed. Obesity results from a chronic imbalance between energy intake and expenditure. ⁹⁴ , ¹³⁵ Genetic, environmental and biological factors contribute to obesity pathogenesis. ¹³⁶ A better understanding of these processes will help develop improved treatment strategies for obesity. Consumption of high‐fat, high‐sugar foods has contributed to the rise in obesity, where a high‐fat diet is often co‐consumed with high salt. ¹⁹ However, the influence of salt on energy balance and subsequently the development of obesity is poorly understood. Recently emerging evidence from mouse and human studies indicates that salt intake is involved in the regulation of energy balance, potentially contributing to the development of obesity via uncertain mechanisms. ¹³⁷ , ¹³⁸ , ¹³⁹

3.1. The role of dietary salt in energy balance regulation

There is very limited direct evidence from human and animal studies linking salt intake with energy balance and obesity risk. A cross‐sectional study with 4283 Australian children reported that high salt intake (14.5 g/d) was associated with increased consumption of sugar‐sweetened beverages, a known risk factor for the development of obesity. ¹²⁹ , ¹³⁰ Indeed, this study showed that for every 1‐g/d increase in salt, an additional 17 g/d of sugary beverages were consumed. ¹⁴⁰ This study suggests that high salt intake induces obesity by stimulating energy intake in children; however, there are no data available from adult populations. Interestingly, an RCT involving both children and adults found that 24‐hour urine sodium levels were significantly higher in overweight and obese subjects, yet food intake was unchanged, as shown by similar 4‐day food intake diary records between the groups. ¹⁴¹ This could suggest a decrease in energy expenditure (EE) by salt overload occurring via unknown mechanisms. Further systemic investigation is required to quantitatively estimate the dietary sodium intake‐obesity relationship under different diet conditions (ie, chow vs. high‐fat diet). It is important to note that widely available self‐reported dietary assessment tools such as 4‐day food diary records, 24‐hour recalls and food frequency questionnaires have all included sodium intake, making the evaluation of this relationship possible. ¹⁴² Moreover, studies have shown that sodium intake obtained from these assessment tools is moderately correlated with 24‐hour urine sodium levels, especially if calculated relative to energy intake (eg, energy density). ¹³² , ¹³³

Animal experiments have provided important initial exploration into the effects of salt intake on energy balance. A high‐salt diet in acute settings (2 weeks) increased food intake in chow‐fed mice. ¹⁴⁴ Similarly, when rats were given a high‐salt diet (3.12% salt), a low‐salt diet (0.06% salt) or a normal‐salt diet (0.5% salt), lower body weight was observed in the high‐salt‐diet rats, which was accompanied by an increase in both food intake and EE. ¹⁴⁵ This suggested a more prominent action of the high‐salt diet on EE. Given that total EE comprises basal metabolic rate, diet‐induced thermogenesis and physical activity, ¹³³ no alteration in motor activity in the high‐salt diet rats suggests that activity is not responsible for the augmented EE. ¹⁴⁵ Other mechanisms may be involved, such as thermogenesis. In fact, a previous study using a rat model reported that high salt intake significantly elevates uncoupling protein 1 (UCP1) expression in brown adipose tissue, resulting in increased EE. ¹⁴⁵ Future studies are needed to determine the mechanisms behind salt‐induced thermogenesis. Importantly, whether this salt‐induced increase in thermogenesis and EE in acute settings can be exploited to counteract obesity is an important area for future investigation.

Several studies in mice and humans have suggested that high salt intake may contribute to thermogenesis and temperature regulation in cold regions, and in turn, cold temperatures may also drive high salt intake. An early study has reported that cold exposure led to elevated salt intake, which in turn induced non‐shivering brown adipose tissue thermogenesis in mice. ¹⁴⁶ Indeed, this association is supported by a recent meta‐analysis that has shown that people living in cold climates consume higher amounts of salt. ¹⁴⁷ , ¹⁴⁸ , ¹⁴⁹ Historically, this increase in salt intake was believed to be attributable to the use of salt as a food preservative. ¹⁵⁰ However, these epidemiological studies point towards an inverse relationship between a cold ambient temperature and salt intake, highlighting the possibility that increased salt consumption may be physiologically necessary for the body to generate more heat in order to effectively adapt to a cold environment. It is noted that long‐term salt treatment may result in different metabolic outcomes from short‐term treatments. For example, mice receiving a high salt intake for 30 weeks had significantly higher body weights as a result of increased fat mass caused by a significantly elevated food intake. ¹⁹ Further studies of short‐ and long‐term alterations in salt intake are needed to better understand the interactions between salt intake and energy homeostasis, especially in obese conditions.

3.2. Molecular mechanisms linking salt intake and metabolic disorders

A recent study has described the significant impact of salt intake on overall metabolism, where high salt intake has been linked to metabolic syndrome via direct and indirect pathways. ¹⁹ Expanding on these metabolic effects, long‐term high dietary salt intake is implicated in the development of metabolic disorders by inducing fructose overproduction, leptin resistance, ghrelin overproduction and insulin resistance, going on to alter NPs and other metabolism‐related hormones (Table 2).

TABLE 2.

Mechanisms underlying the association between high salt intake and metabolic disorders

Disease	Salt‐induced mechanisms	Main conclusion	References
Obesity/metabolic syndrome	Fructose overproduction	High‐salt‐intake‐induced hypertonicity causes fructose production by increasing glucose‐to‐fructose conversion in the polyol pathway in mice	19, 137
	Leptin resistance	High‐salt intake increases leptin production in DIO rats. Fructose overproduction induced by high salt intake leads to increased leptin levels and results in leptin resistance	16, 19, 151
	Ghrelin overproduction	High‐salt intake significantly elevates ghrelin levels and leads to obesity. Ghrelin can alter the taste perception of salt, leading to increased salt intake	138, 152
	NPs stimulated lipolysis and thermogenesis	Exogenous ANP administration improves HFD‐induced IR by promoting WAT browning and alleviating hepatic steatosis. Both ANP and BNP induce lipolysis in a species‐specific manner via their classic NPRA‐cGMP‐PKG and p38 MAPK signalling pathways	15, 18, 153, 154, 155, 156, 157, 158
	High‐salt intake disturbed adiponectin levels	High salt intake fails to elevate the plasma adiponectin levels in salt‐sensitive subjects, but significantly increases adiponectin levels in salt‐resistant subjects	159

Abbreviations: ANP, atrial natriuretic peptide; BNP, B‐type natriuretic peptide; DIO, diet‐induced obesity; HFD, high‐fat diet; IR, insulin resistance; MAPK, mitogen‐activated protein kinase; NPs, natriuretic peptides; NPRA‐cGMP‐PKG, natriuretic peptide receptor A‐cyclic guanosine monophosphate‐protein kinase G; WAT, white adipose tissue.

3.2.1. Fructose overproduction

Fructose is a ketonic simple sugar that is a monomer of one of the major dietary disaccharides, sucrose. Fructose overproduction has been reported to lead to metabolic disorders. ¹⁶⁰ Recently, studies have shown that chronic high salt intake (1% NaCl solution for 30 weeks) significantly elevates osmolarity, which, in turn, leads to fructose formation by increasing glucose‐to‐fructose conversion in mouse models. ¹⁹ Indeed, hypertonicity increased TonEBP activation in the liver, causing activation of the aldose reductase‐sorbitol dehydrogenase pathway. ¹³⁷ The authors further demonstrated that high salt intake led to metabolic syndrome in these wild type mice, involving obesity, hepatic steatosis, IR and elevated BP. ¹³⁷ However, this was absent in fructokinase‐deficient FKA‐A/C knockout mice, ¹⁹ , ¹³⁷ which had defects in metabolizing fructose. Collectively, these findings demonstrated that the negative effects of high salt intake are at least partially dependent on fructose metabolism, whereby high salt intake can lead to metabolic syndrome via fructose overproduction.

3.2.2. High salt intake and leptin resistance

Leptin is an adipose tissue hormone that activates its receptor in the brain to reduce food intake and enhance EE. ¹⁶¹ Leptin resistance refers to a condition where leptin actions are blunted in the target tissues including the brain. Leptin resistance is a hallmark of obesity. ¹⁶² High leptin levels have been reported to lead to leptin resistance. ¹⁶³ There is evidence to suggest that overconsumption of salt can lead to leptin resistance and metabolic syndrome. Dobrian et al reported that high salt intake could modulate leptin levels in a rat model of diet‐induced obesity. ¹⁶ A 2007 study further revealed a link between salt overload, hyperleptinaemia and leptin resistance in rats. ¹⁵¹ Despite no change in body weight, these high‐salt‐fed rats had a higher white fat mass characterized by adipocyte hypertrophy, especially in visceral fat depots. Intriguingly, this occurred in the presence of the activation of both lipogeneses and lipolysis. The detailed mechanism behind this link remains unknown, but a recent study implies that fructose may be required for high‐salt‐induced leptin resistance. ¹⁹ In the high‐salt setting, obesity induced by hyperleptinaemia and leptin resistance could further exacerbate salt‐induced hypertension. It is worth mentioning that currently available data were mainly obtained from animal models; therefore, clinical evidence is needed to confirm the relationship between salt overload and leptin levels in humans.

3.2.3. Ghrelin overproduction

Ghrelin, a gastric‐derived acylated peptide, stimulates appetite to increase energy intake and prevent undernutrition ¹⁶⁴ , ¹⁶⁵ via activation of orexigenic NPY/AgRP neurons in the hypothalamic arcuate nucleus, which subsequently suppress the activity of adjacent pro‐opiomelanocortin (POMC)/CART neurons. ¹⁶⁶ , ¹⁶⁷ Ghrelin overproduction has been implicated in the development of obesity. Seven days of high dietary salt intake has been found to be linked with increased fasting ghrelin levels in an RCT involving 38 nonobese, normotensive subjects. ¹³⁸ Sodium intake levels were directly correlated with ghrelin levels, revealing that elevated ghrelin levels could be one of the key mechanisms in salt‐induced obesity. Moreover, ghrelin has recently been reported to alter the taste perception of salt in the taste cells of fungiform papillae on the tongue, ¹⁵² which is consistent with the finding that germline ghrelin^−/− mice had reduced salt taste sensitivity. ¹⁵² This study suggests that the ghrelin signalling system in the fungiform papillae is an important regulator of salt taste perception, through which it may influence high‐salt‐induced obesity. However, the exact role of ghrelin‐induced altered salt sensation in energy regulation remains to be fully evaluated.

3.2.4. Altered insulin sensitivity

Salt overload and insulin sensitivity

Insulin resistance is defined as a condition in which insulin actions are attenuated in insulin‐sensitive target tissues (eg, skeletal muscle), and is commonly associated with hyperinsulinaemia. ¹⁶⁸ The pathogenesis of IR is complex and has not been fully understood, but obesity/increased adiposity is one of the major risk factors for IR. The effects of dietary salt intake on insulin sensitivity remain controversial; some studies showed that high salt intake induces IR and that reducing salt intake improves insulin sensitivity, ²⁰ , ²¹ while others showed the opposite ¹⁶⁹ (Table 3).

TABLE 3.

The effects of salt on insulin sensitivity in humans

Salt intake level	Salt quantity (converted to the amount of salt in g)	Main conclusion	References
High salt intake	High (11.7 g/d), low (0.58 g/d) salt diet	5‐day high‐sodium diet to healthy subjects led to decreased insulin sensitivity associated with increased circulating free fatty acids	20
	Low‐salt (1.1 g/d) diet followed by high‐salt (11.7 g/d) diet	6‐day high‐salt diet improved insulin sensitivity measured by euglycemic clamps, which was independent of changes in free fatty acids, but associated with reduced SNS activity and aldosterone levels	25, 26
	Daily 4.68 g salt receiving an additional 7.01 g/d salt or a matching placebo in supplement tablets	High salt intake had limited effects on insulin sensitivity in normotensive nonobese subjects	22
	High (11.7 g/d), low (1.17 g/d) salt diet	High salt intake increased insulin sensitivity, as evidenced by reduced insulin levels with no alteration in blood glucose levels in normotensive subjects	169
Low‐salt intake	Reduced urine sodium to <20 mmol/d	Low salt intake led to insulin resistance via RAAS activation in healthy subjects	23
	Low‐salt (1.17 g/d), high‐salt (9.35 g/d) diet	Low sodium diet significantly increased plasma renin activity and aldosterone levels, leading to impaired GSIS without altering insulin sensitivity in normotensive nondiabetic volunteers	24
	Low‐salt (2 g/d), high‐salt (20 g/d) diet	Untreated hypertensive subjects with increased salt intake had higher glucose tolerance via mechanisms that are yet to be determined	170

Abbreviations: GSIS, glucose‐stimulated insulin secretion; RAAS, renin‐angiotensin‐aldosterone system; SNS, sympathetic nervous system.

Data from rodent studies have also shown inconsistency in the relationship between salt overload and insulin sensitivity. A previous study has reported that a 6‐week high‐salt diet led to increased insulin sensitivity in rats, which was associated with increased circulating adiponectin levels. ¹⁷¹ By contrast, several studies using rat models including Dahl salt‐sensitive rats showed that high salt intake induces IR. ²⁰ , ¹⁷² , ¹⁷³ , ¹⁷⁴ More importantly, these studies further suggested that the mechanism underlying the high‐salt‐related IR is likely to be different from obesity‐induced IR; unlike high‐fat‐diet‐induced IR models and Zucker diabetic fatty fa/fa rats which respond to insulin sensitizers such as pioglitazone, ¹⁷⁵ insulin sensitizers did not prevent high‐salt‐related IR. ¹⁷² The exact mechanisms of these differences remain unclear; however, a recent study proposed that impaired microvascular function in skeletal muscle could play a role in the observed high‐salt‐induced IR. ¹⁷⁶

Sodium restriction and insulin sensitivity

Low salt intake has been reported to be associated with IR through mechanisms that are not yet fully understood. However, there is a wealth of literature that shows sodium restriction could produce IR via activation of the RAAS, leading to elevated aldosterone levels. ¹⁷⁷ , ¹⁷⁸ In fact, aldosterone levels are found to be increased in patients with obesity, ¹⁷ and this promotes IR by altering potassium levels, increasing proinflammatory cytokines and decreasing beneficial adiponectin. Inhibition of the RAAS by angiotensin‐converting enzyme inhibitors and angiotensin receptor blockers improves insulin sensitivity and glucose tolerance. ¹⁷⁹ Moreover, as NPs suppress the RAAS and are also linked to insulin sensitivity, it is possible that NPs are involved in salt intake‐related insulin sensitivity by reducing aldosterone levels.

A study involving 150 healthy participants of different ages, sexes and ethnicities found that low salt intake was associated with a high degree of IR, and that a moderate increase in salt intake may increase insulin sensitivity. ²³ Sodium restriction in healthy subjects significantly increased plasma renin activity and aldosterone levels, leading to impaired glucose‐stimulated insulin secretion (GSIS) without altering insulin sensitivity. ²⁴ This finding is in agreement with clinical studies demonstrating that patients with primary aldosteronism had impaired first‐phase GSIS, ¹⁸⁰ and increased insulin clearance. ¹⁸¹ In contrast, a recent clinical study ¹⁸² reported that patients with primary aldosteronism had significantly reduced insulin sensitivity, without altered islet GSIS. ¹⁸² More studies further describe how aldosterone‐deficient mice displayed enhanced insulin secretion without altered insulin sensitivity, and how aldosterone impairs GSIS in isolated islets. ¹⁸³ Together, these findings highlight a direct negative effect of aldosterone on beta‐cell function and provide insights into how low salt intake may produce IR and increase the risk of diabetes by elevating aldosterone levels. In addition to the RAAS‐aldosterone axis, low salt intake can independently activate the SNS, which has also been associated with IR development. ¹⁸⁴ This has been observed in studies via an increase in urine norepinephrine levels in those with low‐salt diets. ¹⁸⁵ , ¹⁸⁶

Given the negative effects of low salt intake on insulin sensitivity, increasing dietary salt has been posited to improve glucose tolerance. Subjects with increased salt intake had higher glucose tolerance ¹⁷⁰ via mechanisms that are yet to be determined. This mixed picture and the significant inconsistencies regarding salt's effects on insulin sensitivity and glucose tolerance may result from differences among studies, such as sample size, ethnic background, duration and doses of salt treatment, methods of evaluating insulin sensitivity, diet types, and presence of comorbidities. For this reason, more clinical studies with large sample sizes, different age groups and diverse ethnic backgrounds are warranted to address the complex relationship between salt and insulin sensitivity. In addition, well‐controlled animal studies involving different salt‐intake regimens (eg, dose and duration) and dietary conditions (standard chow vs. high‐fat diet) would be valuable in deepening the understanding of this area and informing clinical studies. This is important as the knowledge gained from these future clinical and experimental studies will help find the optimal dose and duration of salt reduction in order to maximize efficacy and minimize side effects, and hopefully assist in developing personalized treatment plans for patients with different underlying conditions, such as hypertension and chronic HF.

3.2.5. Altered cardiac NPs

Emerging evidence suggests that NPs play a critical role in mediating thermogenesis, metabolism and insulin sensitivity. ¹⁵ , ¹⁸ , ¹⁵⁵ , ¹⁵⁶ Epidemiological studies have reported that lower circulating NP levels are associated with obesity, IR and type 2 diabetes. ¹⁸ , ¹⁸⁷ , ¹⁸⁸ , ¹⁸⁹ Exogenous ANP administration improved high‐fat‐diet‐induced IR by promoting white adipose tissue browning and alleviating hepatic steatosis. ¹⁵⁴ Both ANP and BNP induce lipolysis ¹⁵³ in a species‐specific manner, ¹⁵⁷ and their lipolytic potency is comparable to that of catecholamines. ¹⁵ Consistent with their role in lipolysis, Bordicchia et al further demonstrated that ANP/BNP could activate the thermogenic program and mitochondrial biogenesis in human brown adipocytes, a process mediated by p38 MAPK signalling pathways. ¹⁵ ANP increased intracellular temperatures in murine cultured adipocytes by markedly increasing UCP1 expression in brown adipose tissue and inguinal/subcutaneous white adipose tissue. ¹⁵⁴ Recent research has also revealed that ANP stimulated white fat browning in the epicardial fat of patients with HF; this process is important as it provided heat directly to the myocardium and protected the failing heart from a hypoperfusion‐induced decrease in temperature. ¹⁵⁸ Thus, NPs represent a novel, critical link between the cardiac system and metabolism. It is worth noting that cold exposure increases circulating NP levels and upregulates NP receptors in brown and white adipocytes, leading to thermogenesis. ¹⁵ Additionally, ANP‐treated mice were more tolerant to cold exposure. ¹⁵⁴ Therefore, we speculate that high‐salt intake‐induced improvement in cold tolerance might be mediated at least partially by NPs.

3.2.6. Other metabolism‐related hormones

Adiponectin

Adiponectin is predominantly secreted by adipocytes. ¹⁹⁰ It exhibits antidiabetic, anti‐inflammatory, and anti‐atherosclerotic effects and is also an insulin sensitizer. ¹⁹¹ Lower circulating adiponectin levels have been shown to be closely associated with type 2 diabetes and coronary heart disease, ¹⁹² and are an independent risk factor for hypertension. ¹⁹³ High salt intake may contribute to metabolic and CVD by disturbing adiponectin levels. A recent intervention study involving 30 healthy subjects showed that 7‐day high salt intake failed to elevate the plasma adiponectin levels in salt‐sensitive subjects, but significantly increased adiponectin levels in salt‐resistant subjects. ¹⁵⁹ Salt sensitivity refers to a phenomenon of different BP response to changes in dietary salt intake. ¹⁹⁴ Normotensive salt‐sensitive subjects are more prone to developing hypertension. Thus, these data suggest that the disturbance of adiponectin may be a new potential mechanism for salt sensitivity.

Glucagon‐like peptide‐1

It is well accepted that glucagon‐like peptide‐1 (GLP‐1) plays important roles in energy homeostasis and glucose metabolism mainly via its actions on inhibiting appetite, increasing insulin secretion in a glucose‐dependent manner and inhibiting gastric emptying. ¹⁹⁵ In addition, GLP‐1 has been shown to reduce water intake in healthy individuals and patients with diabetes, ¹⁹⁶ , ¹⁹⁷ suggesting its involvement in sodium and water homeostasis. ¹⁹⁸ Indeed, GLP‐1 can attenuate high‐salt‐induced volume expansion by increasing renal sodium excretion and urine volume, and decreasing sodium absorption in the gastrointestinal tract, possibly via similar sodium transporters such as NHE‐3. ¹⁹⁸ There is little evidence in the literature showing the impact of dietary salt intake on GLP‐1 levels in the contexts of obesity and diabetes. However, an intervention study with 38 subjects from northern China reported that circulating GLP‐1 levels were elevated with low salt intake and were decreased with high salt intake. ¹⁹⁹ More research is needed to delineate the relationship between salt intake and GLP‐1 levels. Nonetheless, this study highlights the possibility that high salt intake could promote obesity and metabolic syndrome by suppressing GLP‐1 production.

3.2.7. Diuretic medications

Diuretic treatment is a cornerstone for patients with hypertension and HF. ¹⁰⁶ , ²⁰⁰ The impact of diuretics on glucose metabolism was reported previously in several studies which found that thiazide diuretics impaired glucose tolerance, but this effect could be prevented by maintenance of potassium levels. ²⁰¹ Interestingly, the ACCOMPLISH RCT demonstrated that thiazide‐based treatment conferred less CVD protection in normal‐weight than in obese patients. ²⁰² Diuretic chlortalidone was associated with an unexpectedly high cardiovascular event rate in lean patients in the SHEP study. ²⁰³ Additionally, thiazide diuretics can augment IR, intra‐abdominal fat accumulation, and serum uric acid levels. Indeed, diuretics have been found to confer a 35% increased risk of new‐onset diabetes, and this risk rose with the duration of diuretic treatment. ²⁰⁴ In light of these findings, there is some controversy about whether diuretic treatment is a good choice for hypertensive or HF patients with obesity, ²⁰² , ²⁰⁵ underpinning an intriguing dilemma for clinicians.

4. CONCLUSIONS AND FUTURE RESEARCH DIRECTIONS

High salt intake is rife in modern society and has a significant impact on health. This review is purposed with providing the scientific basis for the effects of salt on metabolism and encouraging future clinical trials to explore these pathways and mechanisms in greater depth. This should illuminate therapeutic targets for the development of precision medicines that can improve cardiovascular and metabolic disorders with reduced side effects.

Numerous studies have elucidated the underlying mechanisms of how high salt intake can give rise to CVD. In this review, we have listed the classic mechanisms of hypertension, such as NPs invovlement, DHE‐3‐ and ENaC‐mediated sodium uptake and inflammation, and also updated the list to include high‐salt‐induced disturbances to the gut microbiome and altered neurohormonal factors. Importantly, we described how high salt intake could lead to metabolic disorders via fructose overproduction, leptin resistance, ghrelin overproduction, insulin resistance altered levels of metabolism‐related key hormones. However, studies have rarely assessed whether this salt‐induced metabolic disorder is involved in the pathogenesis of salt‐induced CVD. The metabolic changes could underpin novel mechanisms of high‐salt‐intake‐induced CVD, or they may exacerbate known salt‐related cardiovascular effects. Additionally, this review conveys the importance of noncaloric substances, such as salt, in energy homeostasis. We provide a framework for future studies regarding the effect of salt on energy metabolism, reporting the potential role of salt in regulating EE by stimulating non‐shivering thermogenesis. This was identified in early studies; however, the underlying mechanisms behind this effect have been left unexplored, necessitating further research into salt‐induced thermogenesis. Additionally, we have described how higher salt intake can be linked to positive health effects in some circumstances, mostly in an acute setting. However, given the well‐documented adverse effects of high‐salt diets, these findings should be taken “with a grain of salt”. A potential solution for translating select beneficial effects into therapeutic applications without bringing health complications could be the use of salt substitution diets and the development of novel salt analogues.

AUTHOR CONTRIBUTIONS

Qi Wu queried the research background and wrote the first draft of manuscript. George Burley revised and edited the manuscript. Li‐Cheng Li carried out the literature search on cardiovascular aspects. Yan‐Chuan Shi and Shu Lin conceived the idea. Yan‐Chuan Shi designed the structure of the manuscript, reviewed, edited and finalized the manuscript.

CONFLICT OF INTEREST STATEMENT

The authors declare that they have no competing interests.

PEER REVIEW

The peer review history for this article is available at https://publons.com/publon/10.1111/dom.14980.

Wu Q, Burley G, Li L‐C, Lin S, Shi Y‐C. The role of dietary salt in metabolism and energy balance: Insights beyond cardiovascular disease. Diabetes Obes Metab. 2023;25(5):1147‐1161. doi: 10.1111/dom.14980

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available on request from the corresponding author.