Peter J. Havel

Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans

Studies in animals have documented that, compared with glucose, dietary fructose induces dyslipidemia and insulin resistance. To assess the relative effects of these dietary sugars during sustained consumption in humans, overweight and obese subjects consumed glucose- or fructose-sweetened beverages providing 25% of energy requirements for 10 weeks. Although both groups exhibited similar weight gain during the intervention, visceral adipose volume was significantly increased only in subjects consuming fructose. Fasting plasma triglyceride concentrations increased by approximately 10% during 10 weeks of glucose consumption but not after fructose consumption. In contrast, hepatic de novo lipogenesis (DNL) and the 23-hour postprandial triglyceride AUC were increased specifically during fructose consumption. Similarly, markers of altered lipid metabolism and lipoprotein remodeling, including fasting apoB, LDL, small dense LDL, oxidized LDL, and postprandial concentrations of remnant-like particle-triglyceride and -cholesterol significantly increased during fructose but not glucose consumption. In addition, fasting plasma glucose and insulin levels increased and insulin sensitivity decreased in subjects consuming fructose but not in those consuming glucose. These data suggest that dietary fructose specifically increases DNL, promotes dyslipidemia, decreases insulin sensitivity, and increases visceral adiposity in overweight/obese adults.

Control of energy homeostasis and insulin action by adipocyte hormones: leptin, acylation stimulating protein, and adiponectin

&NA; Adipose tissue performs complex metabolic and endocrine functions. This review will focus on the recent literature on the biology and actions of three adipocyte hormones involved in the control of energy homeostasis and insulin action, leptin, acylation‐stimulating protein, and adiponectin, and mechanisms regulating their production. Results from studies of individuals with absolute leptin deficiency (or receptor defects), and more recently partial leptin deficiency, reveal leptins critical role in the normal regulation of appetite and body adiposity in humans. The primary biological role of leptin appears to be adaptation to low energy intake rather than a brake on overconsumption and obesity. Leptin production is mainly regulated by insulin‐induced changes of adipocyte metabolism. Consumption of fat and fructose, which do not initiate insulin secretion, results in lower circulating leptin levels, a consequence which may lead to overeating and weight gain in individuals or populations consuming diets high in energy derived from these macronutrients. Acylation‐stimulating protein acts as a paracrine signal to increase the efficiency of triacylglycerol synthesis in adipocytes, an action that results in more rapid postprandial lipid clearance. Genetic knockout of acylation‐stimulating protein leads to reduced body fat, obesity resistance and improved insulin sensitivity in mice. The primary regulator of acylation‐stimulating protein production appears to be circulating dietary lipid packaged as chylomicrons. Adiponectin increases insulin sensitivity, perhaps by increasing tissue fat oxidation resulting in reduced circulating fatty acid levels and reduced intramyocellular or liver triglyceride content. Adiponectin and leptin together normalize insulin action in severely insulin‐resistant animals that have very low levels of adiponectin and leptin due to lipoatrophy. Leptin also improves insulin resistance and reduces hyperlipidemia in lipoatrophic humans. Adiponectin production is stimulated by agonists of peroxisome proliferator‐activated receptor‐gamma; an action may contribute to the insulin‐sensitizing effects of this class of compounds. The production of all three hormones is influenced by nutritional status. These adipocyte hormones, the pathways controlling their production, and their receptors represent promising targets for managing obesity, hyperlipidemia, and insulin resistance.

Dietary Fructose: Implications for Dysregulation of Energy Homeostasis and Lipid/Carbohydrate Metabolism

Fructose intake and the prevalence of obesity have both increased over the past two to three decades. Compared with glucose, the hepatic metabolism of fructose favors lipogenesis, which may contribute to hyperlipidemia and obesity. Fructose does not increase insulin and leptin or suppress ghrelin, which suggests an endocrine mechanism by which it induces a positive energy balance. This review examines the available data on the effects of dietary fructose on energy homeostasis and lipid/carbohydrate metabolism. Recent publications, studies in human subjects, and areas in which additional research is needed are emphasized.

Peripheral signals conveying metabolic information to the brain: short-term and long-term regulation of food intake and energy homeostasis.

Numerous peripheral signals contribute to the regulation of food intake and energy homeostasis. Mechano- and chemoreceptors signaling the presence and energy density of food in the gastrointestinal (GI) tract contribute to satiety in the immediate postprandial period. Changes in circulating glucose concentrations appear to elicit meal initiation and termination by regulating activity of specific hypothalamic neurons that respond to glucose. Other nutrients (e.g., amino acids and fatty acids) and GI peptide hormones, most notably cholecystokinin, are also involved in short-term regulation of food intake. However, the energy density of food and short-term hormonal signals by themselves are insufficient to produce sustained changes in energy balance and body adiposity. Rather, these signals interact with long-term regulators (i.e., insulin, leptin, and possibly the orexigenic gastric peptide, ghrelin) to maintain energy homeostasis. Insulin and leptin are transported into the brain where they modulate expression of hypothalamic neuropeptides known to regulate feeding behavior and body weight. Circulating insulin and leptin concentrations are proportional to body fat content; however, their secretion and circulating levels are also influenced by recent energy intake and dietary macronutrient content. Insulin and leptin concentrations decrease during fasting and energy-restricted diets, independent of body fat changes, ensuring that feeding is triggered before body energy stores become depleted. Dietary fat and fructose do not stimulate insulin secretion and leptin production. Therefore, attenuated production of insulin and leptin could lead to increased energy intake and contribute to weight gain and obesity during long-term consumption of diets high in fat and/or fructose. Transcription of the leptin gene and leptin secretion are regulated by insulin-mediated increases of glucose utilization and appear to require aerobic metabolism of glucose beyond pyruvate. Other adipocyte-derived hormones and proteins that regulate adipocyte metabolism, including acylation stimulating protein, adiponectin, diacylglycerol acyltransferase, and perilipin, are likely to have significant roles in energy homeostasis.

Kv1.3 channels are a therapeutic target for T cell-mediated autoimmune diseases.

Autoreactive memory T lymphocytes are implicated in the pathogenesis of autoimmune diseases. Here we demonstrate that disease-associated autoreactive T cells from patients with type-1 diabetes mellitus or rheumatoid arthritis (RA) are mainly CD4+CCR7−CD45RA− effector memory T cells (TEM cells) with elevated Kv1.3 potassium channel expression. In contrast, T cells with other antigen specificities from these patients, or autoreactive T cells from healthy individuals and disease controls, express low levels of Kv1.3 and are predominantly naïve or central-memory (TCM) cells. In TEM cells, Kv1.3 traffics to the immunological synapse during antigen presentation where it colocalizes with Kvβ2, SAP97, ZIP, p56lck, and CD4. Although Kv1.3 inhibitors [ShK(L5)-amide (SL5) and PAP1] do not prevent immunological synapse formation, they suppress Ca2+-signaling, cytokine production, and proliferation of autoantigen-specific TEM cells at pharmacologically relevant concentrations while sparing other classes of T cells. Kv1.3 inhibitors ameliorate pristane-induced arthritis in rats and reduce the incidence of experimental autoimmune diabetes in diabetes-prone (DP-BB/W) rats. Repeated dosing with Kv1.3 inhibitors in rats has not revealed systemic toxicity. Further development of Kv1.3 blockers for autoimmune disease therapy is warranted.

Elevated Free Fatty Acids Induce Uncoupling Protein 3 Expression in Muscle: A Potential Explanation for the Effect of Fasting

The newly described uncoupling protein 3 (UCP3) may make an important contribution to thermogenesis in humans because of its high level of expression in skeletal muscle. Contrary to expectations, fasting, a condition that reduces resting energy expenditure, has been reported to increase UCP3 expression in muscle. We have confirmed that a 10-fold increase in UCP3 mRNA levels occurs in rat quadriceps muscle between 12 and 24 h of food removal. A less consistent twofold increase in muscle UCP2 mRNA levels was observed in animals fasted for up to 72 h. Administration of recombinant leptin to prevent a fall in circulating leptin levels did not eliminate the fasting-induced increase in quadriceps UCP3 expression. Administration of a high dose of glucocorticoid to fed animals to mimic the increase in corticosterone induced by fasting did not reproduce the increase in UCP3 expression observed in fasted animals. In contrast, elevation of circulating free fatty acid levels in fed animals by Intralipid plus heparin infusion caused significant increases in the UCP3/actin mRNA ratio compared with saline-infused fed controls in both extensor digitorum longus (2.01 ± 0.34 vs. 0.68 ± 0.11, P = 0.002) and soleus muscles (0.31 ± 0.07 vs. 0.09 ± 0.02, P = 0.014). We conclude that free fatty acids are a potential mediator of the increase in muscle UCP3 expression that occurs during fasting. This seemingly paradoxical induction of UCP3 may be linked to the use of free fatty acid as a fuel rather than an increased need of the organism to dissipate energy.

Role of adipose tissue in body-weight regulation: Mechanisms regulating leptin production and energy balance

Adipose tissue performs complex metabolic and endocrine functions. Among the endocrine products produced by adipose tissue are tumour necrosis factor alpha, interleukin 6, acylation-stimulating protein and leptin. The present review will focus primarily on mechanisms regulating leptin production and leptin action, and the implications of this regulation in the control of energy balance. Leptin acts in the central nervous system where it interacts with a number of hypothalamic neuropeptide systems to regulate feeding behaviour and energy expenditure. The presence of extreme obesity in animals and human subjects with mutations of the leptin gene or the leptin receptor demonstrates that normal leptin production and action are critical for maintaining energy balance. Insulin is the major regulator of leptin production by adipose tissue. Insulin infusions increase circulating leptin concentrations in human subjects. Plasma leptin levels are markedly decreased in insulin-deficient diabetic rodents, and the low leptin levels contribute to diabetic hyperphagia. Based on in vitro studies, the effect of insulin to stimulate leptin production appears to involve increased glucose metabolism. Blockade of glucose transport or glycolysis inhibits leptin expression and secretion in isolated adipocytes. Evidence suggests that anaerobic metabolism of glucose to lactate does not stimulate leptin production. Alterations in insulin-mediated glucose metabolism in adipose tissue are likely to mediate the effects of energy restriction to decrease, and refeeding to increase, circulating leptin levels. Changes in glucose metabolism may also explain the observation that high-fat meals lower 24h circulating leptin levels relative to high-carbohydrate meals in human subjects, suggesting a mechanism that may contribute to the effects that high-fat diets have in promoting increased energy intake, weight gain and obesity. The decreased circulating leptin observed during energy restriction is related to increased sensations of hunger in human subjects. Thus, decreases in leptin during energy-restricted weight-loss regimens may contribute to the strong propensity for weight regain. A better understanding of the precise mechanisms regulating leptin production and leptin action may lead to new approaches for managing obesity.

Endocrine and metabolic effects of consuming fructose- and glucose-sweetened beverages with meals in obese men and women: influence of insulin resistance on plasma triglyceride responses.

CONTEXT Compared with glucose-sweetened beverages, consumption of fructose-sweetened beverages with meals elevates postprandial plasma triglycerides and lowers 24-h insulin and leptin profiles in normal-weight women. The effects of fructose, compared with glucose, ingestion on metabolic profiles in obese subjects has not been studied. OBJECTIVE The objective of the study was to compare the effects of fructose- and glucose-sweetened beverages consumed with meals on hormones and metabolic substrates in obese subjects. DESIGN AND SETTING The study had a within-subject design conducted in the clinical and translational research center. PARTICIPANTS Participants included 17 obese men (n = 9) and women (n = 8), with a body mass index greater than 30 kg/m(2). INTERVENTIONS Subjects were studied under two conditions involving ingestion of mixed nutrient meals with either glucose-sweetened beverages or fructose-sweetened beverages. The beverages provided 30% of total kilocalories. Blood samples were collected over 24 h. MAIN OUTCOME MEASURES Area under the curve (24 h AUC) for glucose, lactate, insulin, leptin, ghrelin, uric acid, triglycerides (TGs), and free fatty acids was measured. RESULTS Compared with glucose-sweetened beverages, fructose consumption was associated with lower AUCs for insulin (1052.6 +/- 135.1 vs. 549.2 +/- 79.7 muU/ml per 23 h, P < 0.001) and leptin (151.9 +/- 22.7 vs. 107.0 +/- 15.0 ng/ml per 24 h, P < 0.03) and increased AUC for TG (242.3 +/- 96.8 vs. 704.3 +/- 124.4 mg/dl per 24 h, P < 0.0001). Insulin-resistant subjects exhibited larger 24-h TG profiles (P < 0.03). CONCLUSIONS In obese subjects, consumption of fructose-sweetened beverages with meals was associated with less insulin secretion, blunted diurnal leptin profiles, and increased postprandial TG concentrations compared with glucose consumption. Increases of TGs were augmented in obese subjects with insulin resistance, suggesting that fructose consumption may exacerbate an already adverse metabolic profile present in many obese subjects.

Consumption of fructose and high fructose corn syrup increase postprandial triglycerides, LDL-cholesterol, and apolipoprotein-B in young men and women

CONTEXT The American Heart Association Nutrition Committee recommends women and men consume no more than 100 and 150 kcal of added sugar per day, respectively, whereas the Dietary Guidelines for Americans, 2010, suggests a maximal added sugar intake of 25% or less of total energy. OBJECTIVE To address this discrepancy, we compared the effects of consuming glucose, fructose, or high-fructose corn syrup (HFCS) at 25% of energy requirements (E) on risk factors for cardiovascular disease. PARTICIPANTS, DESIGN AND SETTING, AND INTERVENTION: Forty-eight adults (aged 18-40 yr; body mass index 18-35 kg/m(2)) resided at the Clinical Research Center for 3.5 d of baseline testing while consuming energy-balanced diets containing 55% E complex carbohydrate. For 12 outpatient days, they consumed usual ad libitum diets along with three servings per day of glucose, fructose, or HFCS-sweetened beverages (n = 16/group), which provided 25% E requirements. Subjects then consumed energy-balanced diets containing 25% E sugar-sweetened beverages/30% E complex carbohydrate during 3.5 d of inpatient intervention testing. MAIN OUTCOME MEASURES Twenty-four-hour triglyceride area under the curve, fasting plasma low-density lipoprotein (LDL), and apolipoprotein B (apoB) concentrations were measured. RESULTS Twenty-four-hour triglyceride area under the curve was increased compared with baseline during consumption of fructose (+4.7 ± 1.2 mmol/liter × 24 h, P = 0.0032) and HFCS (+1.8 ± 1.4 mmol/liter × 24 h, P = 0.035) but not glucose (-1.9 ± 0.9 mmol/liter × 24 h, P = 0.14). Fasting LDL and apoB concentrations were increased during consumption of fructose (LDL: +0.29 ± 0.082 mmol/liter, P = 0.0023; apoB: +0.093 ± 0.022 g/liter, P = 0.0005) and HFCS (LDL: +0.42 ± 0.11 mmol/liter, P < 0.0001; apoB: +0.12 ± 0.031 g/liter, P < 0.0001) but not glucose (LDL: +0.012 ± 0.071 mmol/liter, P = 0.86; apoB: +0.0097 ± 0.019 g/liter, P = 0.90). CONCLUSIONS Consumption of HFCS-sweetened beverages for 2 wk at 25% E increased risk factors for cardiovascular disease comparably with fructose and more than glucose in young adults.

Fructose consumption: potential mechanisms for its effects to increase visceral adiposity and induce dyslipidemia and insulin resistance

Purpose of review Based on interim results from an ongoing study, we have reported that consumption of a high-fructose diet, but not a high-glucose diet, promotes the development of three of the pathological characteristics associated with metabolic syndrome: visceral adiposity, dyslipidemia, and insulin resistance. From these results and a review of the current literature, we present two potential sequences of events by which fructose consumption may contribute to metabolic syndrome. Recent findings The earliest metabolic perturbation resulting from fructose consumption is postprandial hypertriglyceridemia, which may increase visceral adipose deposition. Visceral adiposity contributes to hepatic triglyceride accumulation, novel protein kinase C activation, and hepatic insulin resistance by increasing the portal delivery of free fatty acids to the liver. With insulin resistance, VLDL production is upregulated and this, along with systemic free fatty acids, increase lipid delivery to muscle. It is also possible that fructose initiates hepatic insulin resistance independently of visceral adiposity and free fatty acid delivery. By providing substrate for hepatic lipogenesis, fructose may result in a direct lipid overload that leads to triglyceride accumulation, novel protein kinase C activation, and hepatic insulin resistance. Summary Our investigation and future studies of the effects of fructose consumption may help to clarify the sequence of events leading to development of metabolic syndrome.