Linking cellular zinc status to body weight and fat mass: mapping quantitative trait loci in Znt7 knockout mice

Zinc transporter 7 (Znt7, Slc30a7) knockout (KO) mice display abnormalities in body weight gain and body adiposity. Regulation of body weight and body fat accumulation is complex, involving multiple genetic and environmental factors. To understand how zinc homeostasis influences body weight and fat deposit and to identify quantitative trait loci (QTLs) that link zinc metabolism to growth and adiposity, we conducted a genome-wide mapping study using male F₂ Znt7 KO mice and wild-type (WT) littermates with a mixed 129P1/ReJ and C57BL/6J genetic background. The mice were fed a semi-purified diet containing 30-mg Zn/kg diet at weaning. Body weights and fat pad weights including epididymal, retroperitoneal, and femoral subcutaneous fat pads were measured at 16 weeks of age. We detected two significant QTLs (p < 0.05) for body weight and fat deposit. One was in the F₂ Znt7 KO population and the other in the F₂ WT population. In Znt7 KO mice, the body weight and fat deposit was significantly linked to a locus on chromosome 7 ranging from 64.3 to 78.3 Mb. In WT mice, a significant linkage of retroperitoneal fat mass was found on chromosome 8 between 14.5 and 63.5 Mb. In addition, several other suggestive QTLs (p < 0.63) for body weight and fat accumulation were detected in Znt7 KO and WT mice. In conclusion, the QTLs identified in this study may provide new hints to uncover the genes linking cellular zinc status to growth and body fat accumulation.     

Zinc transport via ZNT5-6 and ZNT7 is critical for cell surface glycosylphosphatidylinositol-anchored protein expression

Glycosylphosphatidylinositol (GPI)-anchored proteins play crucial roles in various enzyme activities, cell signaling and adhesion, and immune responses. While the molecular mechanism underlying GPI-anchored protein biosynthesis has been well studied, the role of zinc transport in this process has not yet been elucidated. Zn transporter (ZNT) proteins mobilize cytosolic zinc to the extracellular space and to intracellular compartments. Here, we report that the early secretory pathway ZNTs (ZNT5–ZNT6 heterodimers [ZNT5-6] and ZNT7–ZNT7 homodimers [ZNT7]), which supply zinc to the lumen of the early secretory pathway compartments are essential for GPI-anchored protein expression on the cell surface. We show, using overexpression and gene disruption/re-expression strategies in cultured human cells, that loss of ZNT5-6 and ZNT7 zinc transport functions results in significant reduction in GPI-anchored protein levels similar to that in mutant cells lacking phosphatidylinositol glycan anchor biosynthesis (PIG) genes. Furthermore, medaka fish with disrupted Znt5 and Znt7 genes show touch-insensitive phenotypes similar to zebrafish Pig mutants. These findings provide a previously unappreciated insight into the regulation of GPI-anchored protein expression and protein quality control in the early secretory pathway.     

Effects of high-fat diet feeding on Znt8-null mice: differences between β-cell and global knockout of Znt8

Genomewide association studies have linked a polymorphism in the zinc transporter 8 (Znt8) gene to higher risk of developing type 2 diabetes. Znt8 is highly expressed in pancreatic β-cells where it is involved in the regulation of zinc transport into granules. However, Znt8 is also expressed in other tissues including α-cells, where its function is as yet unknown. Previous work demonstrated that mice lacking Znt8 globally were more susceptible to diet-induced obesity (Lemaire et al., Proc Natl Acad Sci USA 106: 14872-14877, 2009; Nicolson et al., Diabetes 58: 2070-2083, 2009). Therefore, the main goal of this study was to examine the physiological impact of β-cell-specific Znt8 deficiency in mice during high-fat high-calorie (HFHC) diet feeding. For these studies, we used β-cell-specific Znt8 knockout (Ins2Cre:Znt8loxP/loxP) and whole body Znt8 knockout (Cre-:Znt8(-/-)) mice placed on a HFHC diet for 16 wk. Ins2Cre:Znt8loxP/loxP mice on HFHC diet had similar body weights throughout the study but displayed impaired insulin biosynthesis and secretion and were glucose intolerant compared with littermate control Ins2Cre mice. In contrast, Cre-:Znt8(-/-) mice became remarkably obese, hyperglycemic, hyperinsulinemic, insulin resistant, and glucose intolerant compared with littermate control Cre- mice. These data show that β-cell Znt8 alone does not considerably aggravate weight gain and glucose intolerance during metabolic stress imposed by an HFHC diet. However, global loss of Znt8 is involved in exacerbating diet-induced obesity and resulting insulin resistance, and this may be due to the loss of Znt8 activity in a tissue other than the β-cell. Thus, our data suggest that Znt8 contributes to the risk of developing type 2 diabetes through β-cell- and non-β-cell-specific effects.     

Mouse zinc transporter 1 gene provides an essential function during early embryonic development

The SLC30 family of cation diffusion transporters includes at least nine members in mammals, most of which have been documented to play a role in zinc transport. The founding member of this family, Znt1, was discovered by virtue of its ability to efflux zinc from cells and to protect them from zinc toxicity. However, its physiological functions remain unknown. To address this issue, mice with targeted knockout of the Znt1 gene were generated by homologous recombination in embryonic stem cells. Heterozygous Znt1 mice were viable. In contrast, homozygous Znt1 mice died in utero soon after implantation due to a catastrophic failure of embryonic development. Although extraembryonic membranes formed around these embryos, the embryo proper failed to undergo morphogenesis past the egg cylinder stage and was amorphous by d9 of pregnancy. Expression of the Znt1 gene was detected predominantly in trophoblasts and in the maternal deciduum during the postimplantation period (d5 to d8). The failure of homozygous Znt1 embryos to develop could not be rescued by manipulating maternal dietary zinc (either excess or deficiency) during pregnancy. However, embryos in Znt1 heterozygous females were approximately 3 times more likely to develop abnormally when exposed to maternal dietary zinc deficiency during later pregnancy than were those in wildtype females. These studies suggest that Znt1 serves an essential function of transporting maternal zinc into the embryonic environment during the egg cylinder stage of development, and further suggest that Znt1 plays a role in zinc homeostasis in adult mice.     

Dietary calcium attenuation of body fat gain during high-fat feeding in mice

Human epidemiological studies have supported the hypothesis that a dairy food-rich diet is associated with lower fat accumulation, although prospective studies and intervention trials are not so conclusive and contradictory data exist in animal models. The purpose of this study was to assess the effects on body weight and fat depots of dairy calcium (12 g/kg diet) in wild-type mice under ad libitum high-fat (43%) and normal-fat (12%) diets and to gain comprehension on the underlying mechanism of dairy calcium effects. Our results show that calcium intake decreases body weight and body fat depot gain under high-fat diet and accelerates weight loss under normal-fat diet, without differences in food intake. No differences in gene or protein expression of UCP1 in brown adipose tissue or UCP2 in white adipose tissue were found that could be related with calcium feeding, suggesting that calcium intake contributed to modulate body weight in wild-type mice by a mechanism that is not associated with activation of brown adipose tissue thermogenesis. UCP3 protein but not gene expression increased in muscle due to calcium feeding. In white adipose tissue there were effects of calcium intake decreasing the expression of proteins related to calcium signalling, in particular of stanniocalcin 2. CaSR levels could play a role in decreasing cytosolic calcium in adipocytes and, therefore, contribute to the diminution of fat accretion. Results support the anti-obesity effect of dietary calcium in male mice and indicate that, at least at the time-point studied, activation of thermogenesis is not involved.     

Carboxyl ester lipase deficiency exacerbates dietary lipid absorption abnormalities and resistance to diet-induced obesity in pancreatic triglyceride lipase knockout mice

This study evaluated the contributions of carboxyl ester lipase (CEL) and pancreatic triglyceride lipase (PTL) in lipid nutrient absorption. Results showed PTL deficiency has minimal effect on triacylglycerol (TAG) absorption under low fat dietary conditions. Interestingly, PTL(-)(/)(-) mice displayed significantly reduced TAG absorption compared with wild type mice under high fat/high cholesterol dietary conditions (80.1 +/- 3.7 versus 91.5 +/- 0.7%, p < 0.05). Net TAG absorption was reduced further to 61.1 +/- 3.8% in mice lacking both PTL and CEL. Cholesterol absorption was 41% lower in PTL(-/-) mice compared with control mice (p < 0.05), but this difference was not exaggerated in PTL(-/-), CEL(-/-) mice. Retinyl palmitate absorption was reduced by 45 and 60% in PTL(-/-) mice (p < 0.05) and PTL(-/-), CEL(-/-) mice (p < 0.01), respectively. After 15 weeks of feeding, the high fat/high cholesterol diet, wild type, and CEL(-/-) mice gained approximately 24 g of body weight. However, body weight gain was 6.2 and 8.6 g less (p < 0.01) in PTL(-/-) and PTL(-/-), CEL(-/-) mice, respectively, despite their consumption of comparable amounts of the high fat/high cholesterol diet. The decrease body weight gain in PTL(-/-) and PTL(-/-), CEL(-/-) mice was attributed to their absorption of fewer calories from the high fat/high cholesterol diet, thereby resulting in less fat mass accumulation than that observed in wild type and CEL(-/-) mice. Thus, this study documents that PTL and CEL serve complementary functions, working together to mediate the absorption of a major portion of dietary fat and fat-soluble vitamin esters. The reduced lipid absorption efficiency due to PTL and CEL inactivation also resulted in protection against diet-induced obesity.     

The cellular and subcellular localization of zinc transporter 7 in the mouse spinal cord

The present work addresses the cellular and subcellular localization of the zinc transporter 7 (ZNT7, SLC30a7) protein and the distribution of zinc ions (Zn2+) in the mouse spinal cord. Our results indicated that the ZNT7 immunoreactive neurons were widely distributed in the Rexed's laminae of the gray matter in all spinal segments examined. The ependyma cells of the central canal and glia cells in the white matter were also shown ZNT7-positive. The ZNT7 immunoreactivity was mainly detected in the perinuclear regions of ZNT7-positive cells in the spinal gray matter. For ependyma cells, the immunoreactivity of ZNT7 was detected in the cytoplasm near the lumina of the central canal. Ultrastructural localization showed that ZNT7 was predominately present in the membrane of the Golgi stacks. The double immunofluorescence studies confirmed this result. Other intracellular organelles including the endoplasmic reticulum, mitochondria and lysosomes were devoid of ZNT7-immunostaining. The chelatable Zn2+ ions in the spinal cord were found predominantly in the terminals of the neuron rather than the cell body in the gray matter. However, overlapping distribution of chelatable Zn2+ ions and ZNT7 was found in the ependyma cells. The present study supports the notion that ZNT7 may function to supply zinc ions to the newly synthesized metalloproteins in the secretory pathway of the spinal neuron and the ependyma cell.     

No effect of dietary calcium on body weight of lean and obese mice and rats

Recent epidemiological and animal studies have led to the hypothesis that low dietary calcium intakes contribute to obesity. Here, we evaluated whether calcium influenced the body weight of normal-weight and obese rodents. All experiments involved female C57BL/6J mice or Sprague-Dawley rats fed normal- or high-energy-density diets (3.8 o 4.7 kcal/g). Calcium intake was manipulated by allowing mice to drink sweetened 30 mM CaCl(2) solution or feeding mice and rats diets differing in calcium content (0.2%, 0.6%, o 1.8% Ca(2+)). Blood samples were taken from rats to confirm that the diets had their intended effects on metabolism. There were no effects of the calcium manipulations on energy intake, body weight, or carcass fat content and no simple elation between calciotropic hormones and body weight. One experiment found a significant decrease in body weight gain of lean and obese rats fed the 1.8% Ca(2+) diet, but we suspect that this was due to forced consumption of the unpalatable diet, reducing growth. These studies provide little support for the hypothesis that dietary calcium contributes to the etiology or maintenance of obesity.     

The Effect of Peripheral Administration of Zinc on Food Intake in Rats Fed Zn-adequate or Zn-deficient Diets

Zinc deficiency induces a striking reduction of food intake in animals. To elucidate the mechanisms for this effect, two studies were connectedly conducted to determine the effects of peripheral administration of zinc on food intake in rats fed the zinc-adequate or zinc-deficient diets for a 3-week period. In study 1, two groups of male Sprague-Dawley rats were provided diets made either adequate (ZA; 38.89 mg/kg) or deficient (ZD; 3.30 mg/kg) in zinc. In study 2, after feeding for 3 weeks, both ZA and ZD groups received intraperitoneal (IP) injection of zinc solution with three levels (0.5, 1.0, and 2.0 mug zinc/g body weight, respectively) and cumulative food intake at 0.5, 1, 2, 4, and 24 h, and plasma hormones concentrations were measured. The results in study 1 showed rats fed the ZD diets revealed symptoms of zinc deficiency, such as sparse and coarse hair, poor appetite, susceptibility to surroundings, lethargy, and small movements. Zinc concentrations in serum, femur, and skeletal muscle of rats fed the ZD diets declined by 26.58% (P < 0.01), 27.32% (P < 0.01), and 24.22% (P < 0.05), respectively, as compared with ZA control group. These findings demonstrated that rat models with zinc deficiency and zinc adequacy had been fully established. The results in study 2 showed that IP administration of zinc in both ZA and ZD rats did not influence food intake at each time points (P > 0.05), although zinc deficiency suppressed food intake. Plasma neuropeptide Y (NPY) was higher, but insulin and glucagon were lower in response to zinc deficiency or zinc administration by contrast with their respective controls (P < 0.05). Leptin, T3, and T4 concentrations were uniformly decreased (P < 0.05) in rats fed the ZD diets in contrast to ZA diets; however, no differences (P > 0.05) were observed during zinc injection. Calcitonin gene-related peptide was unaffected (P > 0.05) by either zinc deficiency or zinc administration. The present studies suggested that zinc administration did not affect short-term food intake in rats even in the zinc-deficient ones; the reduced food intake induced by zinc deficiency was fprobably associated with the depression in thyroid hormones. The results also indicated that NPY and insulin varied conversely during the control of food intake.     

Effect of increased dietary calcium on body weight, food and water intake in oral contraceptive treated female rats

The effects of high calcium diet on body weight in OC treated rats are unknown. This study therefore investigated the effect of increasing dietary calcium from 0.9% to 2.5% on body weight, food ingestion, water intake, heart weight index and renal weight index in female Sprague-Dawley rats treated with a combination of OC steroids (ethinyloestradiol + norgestrel). The rats were assigned into three groups of average of 11 rats each; control, OC-treated and OC + Calcium – treated groups and administered orally for 10 weeks. Food and water intake, body weight, cardiac weight index, left ventricular weight index, renal weight index and serum calcium level were determined. The result shows that OC treated rats had significantly lower serum calcium concentration, body weight gain, food, water and calcium intake than those of the control rats. The OC + Calcium – treated rat had significantly higher serum calcium concentration, food, water and calcium intake but significantly lower body weight than those of the OC - treated rats. OC + Calcium - treated rats had significantly higher water intake, calcium intake and significantly lower body weight and food intake when compared with the control rats. Cardiac weight index and renal weight index was comparable in all groups. In conclusion, combined OC-induced reduction in weight gain might be associated with inhibition of the feeding center and consequent inhibition of the thirst center. Co-administration of dietary calcium augmented the reduction in weight gain seen in OC-treated rats probably by further suppression of the feeding and thirst centers.     

Zinc-deficient rats have more limited bone recovery during repletion than diet-restricted rats

The objective of this study was to investigate the effects of dietary zinc deficiency and diet restriction on bone development in growing rats, and to determine whether any adverse effects could be reversed by dietary repletion. Weanling rats were fed either a zinc-deficient diet ad libitum (ZD; <1 mg zinc/kg) or nutritionally complete diet (30 mg zinc/kg) either ad libitum (CTL) or pair-fed to the intake of the ZD group (DR; diet-restricted) for 3 weeks (deficiency phase) and then all groups were fed the zinc-adequate diet ad libitum for 3, 7, or 23 days (repletion phase). Excised femurs were analyzed for bone mineral density (BMD) using dual-energy x-ray absorptiometry, and plasma was analyzed for markers of bone formation (osteocalcin) and resorption (Ratlaps). After the deficiency phase, ZD had lower body weight and reduced femur BMD, zinc, and phosphorus concentrations compared with DR; and these parameters were lower in DR compared with CTL. Femur calcium concentrations were unchanged among the groups. Reduced plasma osteocalcin in ZD and elevated plasma Ratlaps in DR suggested that zinc deficiency limits bone formation while diet restriction accelerates bone resorption activity. After 23 days of repletion, femur size, BMD, and zinc concentrations remained lower in ZD compared with DR and CTL. Body weight and femur phosphorus concentrations remained lower in both ZD and DR compared with CTL after repletion. There were no differences in plasma osteocalcin concentrations after the repletion phase, but the plasma Ratlaps concentrations remained elevated in DR compared with CTL. In summary, both ZD and DR lead to osteopenia during rapid growth, but the mechanisms appear to be due to reduced modeling in ZD and higher turnover in DR. Zinc deficiency was associated with a greater impairment in bone development than diet restriction, and both deficiencies limited bone recovery during repletion in growing rats.     

Hepatic responses to dietary stress in zinc- and metallothionein-deficient mice

Metallothionein (MT) and zinc are both reported to be protective against oxidative and inflammatory stress and may also influence energy metabolism. The role of MT in regulating intracellular labile zinc, thus influencing zinc (Zn)-modulated protein activity, may be a key factor in the response to stress and other metabolic challenges. The objective of this study was to investigate the influence of dietary zinc intake and MT on hepatic responses to a pro-oxidant stress and energy challenge in the form of a high dietary intake of linoleic acid, an omega-6 polyunsaturated fatty acid. Male MT-null (KO) and wild-type (WT) mice, aged 16 weeks, were given semisynthetic diets containing 16% fat and either 5 (marginally zinc-deficient [ZD]) or 35 (zinc-adequate [ZA]) mg Zn/kg. For comparison, separate groups of KO and WT mice were given a rodent chow diet containing 3.36% fat and 86.6 mg Zn/kg. After 4 months on these diets, the body weights of all mice were equal, but liver size, weight, and lipid content were much greater in the animals that consumed semisynthetic diets compared to the chow diet. The increase in liver size was significantly lower in ZA but not ZD KO mice, compared with WT mice. Principally, MT appears to affect the diet-induced increase in liver tissue but it also influences the concentration of hepatic lipid. Plasma levels of C-reactive protein (CRP), a marker of inflammation, were increased by zinc deficiency in WT mice, suggesting that marginal zinc deficiency is proinflammatory. CRP was unaffected by zinc deficiency in KO mice, indicating a role for MT in modulating the influence of zinc. Neither zinc nor MT deficiency affects the level of soluble liver proteins, as determined using two-dimensional (2D) gel proteomics. This study highlights the close association between zinc and MT in the manifestation of stress responses.     

Dietary diacylglycerol suppresses high fat and high sucrose diet-induced body fat accumulation in C57BL/6J mice

Diacylglycerol (DG) comprises up to approximately 10% of various edible oils. In the present study, we examined the effects of dietary DG consisting mainly of 1,3-species on body weight, body fat accumulation, and mRNA levels of various genes involved in energy homeostasis in obesity-prone C57BL/6J mice. Five-month feeding with the high triacylglycerol (TG) diet (30% TG + 13% sucrose) resulted in significant increases in body weight, visceral fat accumulation, and circulating insulin and leptin levels compared with mice fed the control diet (5% TG). Compared with mice fed the high TG diet, body weight gain and visceral fat weight were reduced by 70% and 79%, respectively, in those fed the high DG diet (30% DG + 13% sucrose). In addition, circulating leptin and insulin levels were reduced to the respective control levels. Compared with high TG feeding, high DG feeding suppressed the elevation of leptin mRNA expression in adipose tissue, and up-regulated acyl-coenzyme (Co)A oxidase and acyl-CoA synthase mRNA expression in the liver. These results indicate that dietary DG is beneficial for suppression of high fat diet-induced body fat accumulation. Furthermore, it is suggested that structural differences in DG and TG, but not the composition of fatty acid, markedly affect nutritional behavior of lipids. -- Murase, T., T. Mizuno, T. Omachi, K. Onizawa, Y. Komine, H. Kondo, T. Hase, and I. Tokimitsu. Dietary diacylglycerol suppresses high fat and high sucrose diet-induced body fat accumulation in C57BL/6J mice. J. Lipid Res. 2001. 42: 372--378.     

Growth and body composition changes in mice selected for high post-weaning weight gain on two levels of feeding

Summary Two lines of mice were selected for high post-weaning weight gain (3 to 6 weeks) adjusted for 3 week weight. One line (F) was grown on freely available food and the other (S) on a feeding scale set at the same level for all mice. Food intake of the S line averaged 80% of the F line. The realised heritabilities after 6 generations of selection were 0.38±0.06 and 0.33±0.07 for the F and S lines, respectively. In generation 7, mice from the F and S lines and from an unselected control line (C) were compared on both free and set levels of feeding from 3 weeks to 9 weeks of age. Measurements taken were growth rate, appetite, food conversion efficiency (weight gain/food intake) and body composition (fat, protein, ash, water). The F and S lines grew more rapidly and efficiently than the C line on both levels of feeding, each line performing best on the level of feeding on which it was selected. The average genetic correlation between growth rates of the same line on the two feeding levels was 0.54±0.10. The F line grew 19% faster and was 9% more efficient than the S line on free feeding but the S line grew 15% faster and was 15% more efficient than the F line on set feeding. Relative to the C line, food intake per day on free feeding was 4% higher in the F line and 6% lower in the S line. There was no difference between the lines in food intake/g body weight. The rate of deposition of all body components increased in both selection lines. In the F, S and C lines respectively, efficiencies of gains in body components (10²x gain/food) were 1.79, 1.31 and 1.06 for fat, 1.53, 1.63 and 1.22 for protein and 5.88, 6.45 and 4.98 for protein + water. Apparently energy lost as heat was reduced in both the F and S lines. The partitioning of energy retained was altered in favour of more fat in the F line and more protein in the S line.     

Effect of total colectomy and PYY infusion on food intake and body weight in rats

PYY (3-36) is postulated to act as a satiety factor in the gut-hypothalamic pathway to inhibit food intake and body weight gain in humans and rodent models. We determined the effect of 14-day continuous intravenous infusion of PYY (3-36) (175 microg/kg/day) on food intake and body weight gain in colectomized male Wistar rats. Colectomy caused an increase in plasma PYY levels at 7 days which was reduced at 14 days but still significantly elevated compared to basal preoperative values. Animals treated with continuous PYY (3-36) infusion had significantly elevated PYY levels compared to the control group throughout the whole experiment, but showed a similar pattern of food intake and body weight gain. In conclusion, although continuous intravenous infusion is the most physiologically relevant method to mimic high postprandial PYY levels, we did not observe any significant effect on food intake and body weight gain in non-food deprived colectomized animals. This suggests that PYY has, if at all, only a minor role in food intake in rats.     

Effects of atypical antipsychotic drugs on body weight and food intake in dopamine D2 receptor knockout mice

Many atypical antipsychotic drugs cause weight gain, but the mechanism of this weight gain is unclear. To dissect the role of the dopamine D2 receptor (D2R), an important receptor in the pharmacology of antipsychotic drugs, we analyzed the effect of olanzapine, risperidone, and ziprasidone on changes in body weight and food intake in male wild-type (WT) and D2R knockout (D2R^−/−) mice. The oral delivery of atypical antipsychotics, olanzapine (5 and 10 mg/kg), risperidone (0.1 and 1.0 mg/kg) and ziprasidone (10 and 20 mg/kg) in both strains mice for 2 weeks suppressed body weight gain, except for olanzapine treatment in D2R^−/− mice. Olanzapine treatment suppressed body weight gain and decreased food intake in WT mice, but also reduced fat body mass and locomotor activity, whereas D2R^−/− mice did not show these changes. Ziprasidone and risperidone treatment produced similar responses in WT and D2R^−/− mice. These data suggest the involvement of D2R in the effect of olanzapine on metabolic regulation. Further studies are required to explore the implications of D2R activity in antipsychotic-mediated metabolic complications.     

Zinc deficiency in man: its origins and effects

The occurrence of zinc deficiency in man remained unsuspected until the 1960s. Since then, however, our understanding of the clinical importance of human zinc deficiency has grown rapidly. Zinc depletion has been demonstrated or suggested to be responsible for a variety of clinical features, ranging from minor aberrations of normal growth patterns and subtle impairments of taste perception to life-threatening disease states. The latter have been observed most frequently as a result of an inherited defect in zinc absorption and from feeding intravenously without adding zinc to the infusates. Notable clinical features of severe zinc deficiency states include a florid acro-orificial rash, behavioural changes, poor appetite, severe disturbance of normal growth and development, impaired reproductive performance, and frequent infections associated with abnormalities of the immune system. In general, the biochemical correlates of these clinical features remain poorly defined. While the clinical and laboratory diagnosis of severe zinc deficiency states is quite straightforward, existing techniques are inadequate for the detection of sub-optimal zinc nutrition. This difficulty presents a major challenge as there is evidence that mild or moderate zinc deficiency states are quite common in certain population groups. Though there is reason for particular concern about the zinc status of some socially deprived groups, inadequate zinc intake is also a potential problem in more affluent population groups. The occurrence of zinc deficiency is frequently associated with dietary factors that have an unfavourable effect on zinc absorption, for example phytate, and with a variety of special circumstances including premature delivery. There is evidence that the absorption of zinc from human milk is especially favourable. There is an outstanding need for further research to achieve a clearer understanding of the origins, incidence and effects of human zinc deficiency.     

Reduced food intake and body weight in mice deficient for the G protein-coupled receptor GPR82

G protein-coupled receptors (GPCR) are involved in the regulation of numerous physiological functions. Therefore, GPCR variants may have conferred important selective advantages during periods of human evolution. Indeed, several genomic loci with signatures of recent selection in humans contain GPCR genes among them the X-chromosomally located gene for GPR82. This gene encodes a so-called orphan GPCR with unknown function. To address the functional relevance of GPR82 gene-deficient mice were characterized. GPR82-deficient mice were viable, reproduced normally, and showed no gross anatomical abnormalities. However, GPR82-deficient mice have a reduced body weight and body fat content associated with a lower food intake. Moreover, GPR82-deficient mice showed decreased serum triacylglyceride levels, increased insulin sensitivity and glucose tolerance, most pronounced under Western diet. Because there were no differences in respiratory and metabolic rates between wild-type and GPR82-deficient mice our data suggest that GPR82 function influences food intake and, therefore, energy and body weight balance. GPR82 may represent a thrifty gene most probably representing an advantage during human expansion into new environments.