Open access Editorial Open Heart: first published as 10.1136/openhrt-2017-000676 on 1 July 2018. Downloaded from Role of dietary histidine in the prevention of obesity and metabolic syndrome James J DiNicolantonio,1 Mark F McCarty,2 James H OKeefe 1 To cite: DiNicolantonio JJ, HISTIDINE SUPPLEMENTATION AMELIORATES histidine dose dependently increases hypo- McCarty MF, OKeefe JH. Role of METABOLIC SYNDROME thalamic levels of histamine as well as hypo- dietary histidine in the prevention of obesity and A recent Chinese supplementation study, in thalamic activity of histidine decarboxylase, metabolic syndrome. Open Heart which obese middle-aged women diagnosed the enzyme which converts histidine to hista- 10 2018;5:e000676. doi:10.1136/ with metabolic syndrome received 12 weeks mine. Such administration also inhibits food openhrt-2017-000676 of supplemental histidine (2 g, twice daily) or consumption—an effect that is blocked in matching placebo, achieved remarkable find- animals pretreated with an irreversible inhib- 1 Accepted 24 April 2018 ings. Insulin sensitivity improved significantly itor of histidine decarboxylase. in the histidine-supplemented subjects, and Neuronal histamine release in the hypo- this may have been partially attributable to thalamus is subject to feedback regulation loss of body fat. Body mass index (BMI), waist by presynaptic H3 receptors. In rodent circumference and body fat declined in the studies, antagonists and inverse agonists for histidine-supplemented group relative to the these receptors have been shown to mark- placebo group; the average fat loss in the histi- edly amplify hypothalamic histamine levels, dine group was a robust 2.71 kg. Markers of suppress feeding, decrease body weight and systemic inflammation such as serum tumour enhance metabolic rate.11–15 Such agents may necrosis factor-alpha (TNF-α) and inter- have clinical potential for managing obesity. leukin (IL)-6, non-esterified fatty acids and The clinical relevance of these find- http://openheart.bmj.com/ oxidative stress also decreased in the histidine ings is further suggested by evidence that group. Subsequently, precisely parallel findings use of prescription antihistamines (H1 were reported in female rats rendered obese blockers), or of antipsychotic drugs that also 2 with a high-fat diet. inhibit H1, is associated with an increased risk for obesity.8 16 Of related interest is a BRAIN HISTAMINE INFLUENCES APPETITE AND recent Chinese cross-sectional epidemi- METABOLIC RATE ology correlating dietary histidine inversely with BMI, waist circumference and various These intriguing findings were not altogether on September 29, 2021 by guest. Protected copyright. unexpected, as earlier rodent studies had markers of metabolic syndrome, in both shown that supplemental histidine tends to sexes; this finding remained valid whether inhibit food intake, via an impact on the hypo- daily histidine intake was expressed in abso- thalamus that is mediated by the neurotrans- lute terms, or after adjustment for protein 17 mitter histamine.3–6 Acting via H1 receptors and other dietary values. In a cross-sectional in the ventromedial and paraventricular hypo- study enrolling female Japanese students, thalamic nuclei, histamine suppresses feeding daily histidine intake, as well as the ratio to behaviour, promotes adipocyte lipolysis via histidine to total dietary protein, correlated sympathetic activation and raises metabolic inversely with daily calorie intake after adjust- 18 rate.3 7 8 These effects are analogous to those ment for other dietary factors ; this finding 1 Department of Preventive of leptin on the brain, and indeed histamine evidently is consistent with the possibility Cardiology, Saint Lukes Mid has been shown to be a key mediator of leptin that increased brain histidine uptake can America Heart Institute, Kansas 4 9 City, Missouri, USA signalling in the hypothalamus. Leptin trig- aid appetite control in humans, as it does in 2Catalytic Longevity, Encinitas, gers histamine release in the hypothalamus, rodents. Moreover, a cross-sectional epidemi- California, USA and histamine in turn prevents the downreg- ological study has found that 24 hours urinary ulation of leptin receptors which mediates excretion of histidine correlates inversely with Correspondence to leptin resistance. Crucially, whether adminis- BMI—likewise pointing to a possible role for Dr James J DiNicolantonio; 19 jjdinicol@ gmail. com tered intraperitoneally or intraventricularly, histidine in control of energy balance. DiNicolantonio JJ, et al. Open Heart 2018;5:e000676. doi:10.1136/openhrt-2017-000676 1 Open Heart Open Heart: first published as 10.1136/openhrt-2017-000676 on 1 July 2018. Downloaded from BRAIN HISTAMINE REGULATES GLUCONEOGENESIS primarily by BCAA levels. This observation may be perti- The amplification of brain histamine activity achievable nent to cross-sectional studies concluding that plasma with supplemental histidine, in addition to controlling levels of BCAAs are elevated in those with type 2 diabetes, appetite, also provokes a brain signal to the liver that metabolic syndrome and/or obesity.35–40 Moreover, decreases the expression of gluconeogenic enzymes— several prospective studies have found that plasma most notably glucose-6-phosphatase—and thereby levels of BCAAs likewise correlated positively with type 2 reduces hepatic glucose output.20 A neural signal to diabetes risk.41–43 Whereas elevated BCAAs might plau- Kupffer cells boosts their secretion of IL-6; this acts on sibly be an effect of metabolic syndrome,44 it is also plau- hepatocytes to induce activating tyrosine phosphorylation sible that such elevations could promote weight gain and of Stat3, which in turn transcriptionally represses gluco- impair glycaemic control by impeding histidine’s trans- neogenic enzyme expression.20 21 Intracerebral insulin port into the brain. Indeed, a recent Mendelian rando- works in a complementary and analogous manner to misation analysis concludes that elevated plasma levels of restrain hepatic glucose output.22 23 These considerations BCAA are likely to be true mediators of increased risk for suggest that supplemental histidine could aid glycaemic type 2 diabetes.45 This phenomenon would be analogous control in diabetics by downregulating hepatic glucose to the well-known ability of high plasma levels of neutral output—in addition to favourable effects on periph- amino acids to impede brain serotonin production from eral insulin sensitivity reflecting histidine’s antiobesity/ tryptophan.46 anti-inflammatory actions. It is notable that, in the clin- With respect to dietary intakes of BCAAs, a recent anal- ical study evaluating supplemental histidine in women ysis of three large prospective cohort studies has concluded with metabolic syndrome, fasting glucose fell from that calorie-adjusted intakes of BCAAs correlate posi- 5.9 mM at baseline to 5.1 mM after supplementation.1 tively with risk for onset of type 2 diabetes.47 Although And in mice rendered diabetic by streptozotocin admin- this correlation continued to hold after correction for istration (a model of type 1 diabetes), plasma glucose a range of covariates, it was substantially attenuated, averaged 14.3 mM in those who had received histidine though not eliminated, by adjustment for BMI—consis- in water at 1 g/L for 4 weeks, as opposed to 20.6 mM tent with the possibility that elevated BCAA intake was in those receiving regular water.24 (Plasma glucose in interfering with histidine-dependent central mechanisms healthy control mice was 6.3 mM.) A reduction in hepatic for regulating appetite and glycaemic control. However, glucose output seems likely to be largely responsible for a smaller Japanese prospective study reached the oppo- this effect. site conclusion—that higher dietary intakes of BCAAs predicted lower risk for diabetes.48 Arguably, the true dietary determinant of risk might be the ratio of histidine ANTI-INFLAMMATORY EFFECTS to BCAAs or total neutral amino acids; in this case, such http://openheart.bmj.com/ Supplemental histidine also appears to have anti-inflam- a ratio, in the diet or in plasma, might better predict risk matory effects on tissues that are not mediated centrally than either histidine or BCAAs per se. and independent of its impact on weight control, as suggested by rodent and cell-culture studies.2 24–27 Histi- dine, as well as its derivative carnosine, can exert antiox- CAUTIONS idant effects that reflect its ability to scavenge free radi- Supplemental histidine may have the potential to cals, quench singlet oxygen and chelate free transition increase histamine production by gastric enterochro- 28–30 metals. However, it should be noted that histidine maffin cells and by mast cells. Indeed, one rat study has on September 29, 2021 by guest. Protected copyright. availability is not rate limiting for carnosine synthesis.31 found that stomach levels of histamine are increased Recent prospective epidemiology has found that higher as histidine intake increases beyond normal dietary 49 serum histidine levels predict lower risk for coronary levels. Hence, in susceptible individuals, supple- disease in the subsequent years.32 The impact of dietary mental histidine could conceivably increase risk for histidine on progression of atherosclerosis in rodents has peptic ulcers by boosting gastric acid secretion. If this not yet been studied. proves to be the case, supplemental histidine might be contraindicated in those prone to such ulcers or should be administered