NCLX pumps up the heat

Mitochondrial Ca²⁺ signaling is a well-appreciated regulator of cell metabolism and energy production. A major function of mitochondria in brown adipose tissue (BAT) is thermogenesis. Assali et al. offer new insights into how the mitochondrial Ca²⁺ extrusion mediator NCLX is crucial for BAT survival and thermogenesis.     

Plants at high altitude exhibit higher component of alternative respiration

Total respiration, capacities of cytochrome (CytR) and alternative respiration (AR) were studied in two varieties of barley (Horedum vulgare) and wheat (Triticum aestivum) each and one variety of pea (Pisum sativum) at low (Palampur; 1300 m) and high altitudes (Kibber; 4200 m). Similar studies were carried out in naturally growing Rumex nepalensis and Trifoilum repenses at Palampur, Palchan (2250 m) and Marhi (3250 m). All the plants species exhibited lower CytR but significantly higher AR capacity at high altitude (HA) (72-1117% higher) as compared to those at low altitude (LA). Glycolytic product, pyruvate and tricarboxylic acid cycle intermediate, citrate increased with increase in altitude. While the role of these metabolites in relation to HA biology is discussed, significantly higher AR at HA is proposed to be an adaptive mechanism against the metabolic perturbations wherein it might act to lower reactive oxygen species and also provides metabolic homeostasis to plants under the environment of HA.     

Haematology and erythrocyte metabolism in man at high altitude: an Aymara-Quechua comparison

In the course of haematological and biological investigations among Aymara and Quechua populations in Bolivia, an anthropological study of the erythrocytary respiratory function was carried out on the two groups at two altitudes: 3,600 m and 450 m. A difference in the intensity of the biological variations of the two populations is observed at high altitude. In the Quechuas, as in any lowland native, the adaptative phenomena are totally and quickly reversible. In the Aymaras, we detected the existence of more marked haematological and biochemical characters: moderate polycythemia, hyperhaemoglobinemia, microcytosis, metabolical hyperactivity with accumulation of 2-3 di-phosphoglycerate and ATP, and methaemoglobinemia with a drop in the activity of the methaemoglobin reductases. The Aymaras preserve some of those characters (methaemoglobinemia excepted) when they settle in lowlands.     

Effect of beta-adrenergic blockade on plasma lactate concentration during exercise at high altitude

When unacclimatized lowlanders exercise at high altitude, blood lactate concentration rises higher than at sea level, but lactate accumulation is attenuated after acclimatization. These responses could result from the effects of acute and chronic hypoxia on beta-adrenergic stimulation. In this investigation, the effects of beta-adrenergic blockade on blood lactate and other metabolites were studied in lowland residents during 30 min of steady-state exercise at sea level and on days 3, 8, and 20 of residence at 4300 m. Starting 3 days before ascent and through day 15 at high altitude, six men received propranolol (80 mg three times daily) and six received placebo. Plasma lactate accumulation was reduced in propranolol- but not placebo-treated subjects during exercise on day 3 at high altitude compared to sea-level exercise of the same percentage maximal oxygen uptake (VO2max). Plasma lactate accumulation exercise on day 20 at high altitude was reduced in both placebo- and propranolol-treated subjects compared to exercise of the same percentage VO2max performed at sea level. The blunted lactate accumulation during exercise on day 20 at high altitude was associated with reduced muscle glycogen utilization. Thus, increased plasma lactate accumulation in unacclimatized lowlanders exercising at high altitude appears to be due to increased beta-adrenergic stimulation. However, acclimatization-induced changes in muscle glycogen utilization and plasma lactate accumulation are not adaptations to chronically increased beta-adrenergic activity.     

White-to-brown transdifferentiation of omental adipocytes in patients affected by pheochromocytoma

In all mammals, white adipose tissue (WAT) and brown adipose tissue (BAT) are found together in several fat depots, forming a multi-depot organ. Adrenergic stimulation induces an increase in BAT usually referred to as “browning”. This phenomenon is important because of its potential use in curbing obesity and related disorders; thus, understanding its cellular mechanisms in humans may be useful for the development of new therapeutic strategies. Data in rodents have supported the direct transformation of white into brown adipocytes. Biopsies of pure white omental fat were collected from 12 patients affected by the catecholamine-secreting tumor pheochromocytoma (pheo-patients) and compared with biopsies from controls. Half of the omental fat samples from pheo-patients contained uncoupling protein 1 (UCP1)-immunoreactive-(ir) multilocular cells that were often arranged in a BAT-like pattern endowed with noradrenergic fibers and dense capillary network. Many UCP1-ir adipocytes showed the characteristic morphology of paucilocular cells, which we have been described as cytological marker of transdifferentiation. Electron microscopy showed increased mitochondrial density in multi- and paucilocular cells and disclosed the presence of perivascular brown adipocyte precursors. Brown fat genes, such as UCP1, PR domain containing 16 (PRDM16) and β3-adrenoreceptor, were highly expressed in the omentum of pheo-patients and in those cases without visible morphologic re-arrangement. Of note, the brown determinant PRDM16 was detected by immunohistochemistry only in nuclei of multi- and paucilocular adipocytes. Quantitative electron microscopy and immunohistochemistry for Ki67 suggest an unlikely contribution of proliferative events to the phenomenon. The data support the idea that, in adult humans, white adipocytes of pure white fat that are subjected to adrenergic stimulation are able to undergo a process of direct transformation into brown adipocytes. This article is part of a Special Issue entitled Brown and White Fat: From Signaling to Disease.     

Species specific chlorophyll a fluorescence-temperature profile at high temperatures in the leaves

Chlorophyll a (Chl a) fluorescence-temperature profile in the region of 20–80°C was recorded for fourteen different plant species. In all the species studied, there was a rise in the fluorescence intensity in the region of 45–50°C and around 55°C the fluorescence intensity started to decline. In four of the species (Acacia melanoxylon, Ervatamia montana, Eucalyptus tertecornius and Azardicta indica) tested, there was a secondary rise in the fluorescence intensity around 65–70°C whereas in all other species a sharp decline in the fluorescence intensity was observed at this point. These changes in the fluorescence intensity at high temperatures (65–70°C) appear to be species specific and cannot be explained either in terms of changes in the stoichiometry between the two photosystems or in terms of Chl a fluorescence emission from photosystem I (PS I) at higher temperatures. This conclusion is supported by following observations: (1) there was no definite correlation between the Chl a/Chl b ratio and the pattern of fluorescence-temperature profile at high temperatures; (2) the sun and shade plants of the same species had a similar pattern of fluorescence-temperature profile; and (3) preferential excitation of PS I did not alter the fluorescence-temperature profile.Abbreviations Chl chlorophyll - PS photosystem     

Adipose tissue development--impact of the early life environment

Increasing experimental and observational evidence in both animals and humans suggests that early life events are important in setting later fat mass. This includes both the number of adipocytes and the relative distribution of both brown and white adipose tissue. Brown adipose tissue is characterised as possessing a unique uncoupling protein (UCP)1 which enables the rapid generation of large amounts of heat and is most abundant in the newborn. In large mammals such as sheep and humans, brown fat that is located around the major internal organs, is largely lost during the postnatal period. However, it is retained in small and discrete areas into adulthood when it is sensitive to environmental cues such as changes in ambient temperature or day length. The extent to which brown adipose tissue is lost or replaced by white adipose tissue and/or undergoes a process of transdifferentiation remains controversial. Small amounts of UCP1 can also be present in skeletal muscle which now appears to share the same common precursor cell as brown adipose tissue. The functional consequences of UCP1 in muscle remain to be confirmed but it could contribute to dietary induced thermogenesis. Challenges in elucidating the primary mechanisms regulating adipose tissue development include changes in methylation status of key genes during development in different species, strains and adipose depots. A greater understanding of the mechanisms by which early life events regulate adipose tissue distribution in young offspring are likely to provide important insights for novel interventions that may prevent excess adiposity in later life.     

Uncoupling protein in human brown adipose tissue mitochondria. Isolation and detection by specific antiserum

A protein of Mr 32 000 has been isolated from human infant brown adipose tissue mitochondria following the procedure used to purify the uncoupling protein from rat brown adipose tissue mitochondria. A specific antiserum has been raised against the human 32 kDa protein, and used to detect it by probing mitochondrial proteins separated by SDS-PAGE. The protein is present in large amounts in brown adipose tissue but is undetectable in human liver, heart or white adipose tissue. It has strong immunological cross-reactivity with rat brown adipose tissue uncoupling protein.     

Brown and white adipose tissue lipid composition in three successive progenies of rats: Effects of ethanol exposure

The effect of ethanol exposure on the fatty acid composition of brown and white adipose tissue in three successive rat progenies at the end of an experimental period (24 weeks) was studied. Ethanol‐treated rats received a standard rat chow diet and 5, 10 and 15% ethanol in the ad libitum drinking fluid over 3 successive weeks. Then a concentration of 20% ethanol was maintained for 5 additional weeks up to the end of the experimental period. The males and females in the ethanol treated group were mated to obtain the 1st generation of offspring. Then female and male rats from the 1st generation were mated to obtain the 2nd generation. Finally, males and females from the 2nd generation were mated to obtain the 3rd generation of ethanol treated rats. Another group served as control and received only water and a standard rat chow diet. The control group was handled in the same way as the other experimental groups. In the 1st and 2nd generations the percentage of stearic acid (18:0) decreased and palmitoleic (16:ln7) and oleic acid (18:ln9) increased in both adipose tissues of ethanol‐treated rats with respect to control. Additionally, n‐3 and n‐6 series were reduced both in brown and white adipose tissues. In the 3rd generation the fatty acid composition of the white adipose tissue was similar to that of control rats. Thus, no significant difference in essential fatty acids and oleic acid (18:ln9) were found. However, the fatty acid composition of the brown adipose tissue, in the 3rd generation, was similar to that observed in the 1st and 2nd generation. Thus, a decrease in essential fatty acids and an increase in oleic acid (18:ln9) was found. This suggests adaptation to ethanol consumption during successive progenies in white adipose tissue. However, in brown adipose tissue the values indicate a triglyceride storing during the thermogenesis, which is more important to newborns.     

Differential metabolism of brown adipose tissue in newborn rabbits in relation to position in the litter huddle

Competition for resources can contribute importantly to the early development of individual differences in behavioral and physiological phenotypes. In newborn rabbits, littermates compete for thermally favorable positions within the litter huddle. As brown adipose tissue (BAT) is the principal site of thermogenesis in such altricial young, we investigated differences in rabbit pups’ growth and morphological differences in BAT associated with position within the huddle. We formed three treatment groups (7 litters/group): GI—birth (pups killed at birth); GII—chronic thermal challenge (pups killed after exposure to a moderately cold environmental during postnatal days 1–3); GIII—acute thermal challenge (as for GII but pups killed after an additional 30 min exposure to a very cold environment on postnatal day 3). Interscapular BAT was removed at death for histological analysis, and triglyceride concentrations measured in serum. Pups occupying central positions in the huddle had higher skin temperatures, obtained more milk, and were more efficient at converting this into body mass, than pups occupying peripheral positions. There was no significant difference in BAT morphology or triglyceride concentrations between pups at birth, nor between central and peripheral pups chronically exposed to moderate cold until postnatal day 3. However, during acute cold exposure at this age, peripheral pups were less able to maintain their body temperature, they depleted BAT fat reserves almost completely, and they had lower serum concentrations of triglycerides than central pups. These findings confirm the contribution of early sibling relations to individual differences in growth and metabolic processes associated with thermoregulation in newborn rabbits.     

Neonatal mortality and leanness in mice lacking the ARID transcription factor Mrf-2

Proteins containing the ARID (AT-rich interaction domain) DNA-binding motif regulate gene expression and differentiation in fungi, plants, and animals. This report describes phenotypes resulting from targeted disruption of the ARID gene Mrf-2. Homozygous loss of Mrf-2 resulted in a high rate of neonatal mortality that was partially strain-dependent: survival of Mrf-2(-/-) pups ranged from 6.4% on the 129S1 genetic background to 38% on a mixed 129S1.C57Bl/6J background. Loss of Mrf-2 expression did not affect embryonic survival, embryonic growth or birth weight. Lipid accumulation was severely reduced in brown adipose of Mrf-2(-/-) neonates at 24h of age, however, and Mrf-2(-/-) mice weighed significantly less than controls from postnatal day five onward. Adult Mrf-2(-/-) mice were lean, with significant reductions in brown and white adipose tissues, and in the percentage of body fat. Mrf-2(-/-) and Mrf-2(+/-) mice were also resistant to weight gains and obesity when maintained on high-fat diets. These phenotypes suggest that Mrf-2 is essential for accumulation of lipid stores in postnatal life.     

Effects of running training on in vitro brown adipose tissue thermogenesis in rats

Brown adipose tissue (BAT) is a major site of nonshivering thermogenesis (NST) during cold acclimation for most mammals. Repetitive nonthermal stress such as immobilization has been shown to enhance the capacity of NST as cold acclimation. In the present study, the effects of running training, another type of nonthermal stress, were investigated on in vitro thermogenesis and the cellularity of interscapular BAT in rats. The rats were subjected to treadmill running for 30 min daily at 30 m/min under 8° inclination for 4–5 weeks. In vitro thermogenesis was then measured in minced tissue blocks incubated in a Krebs-Ringer phosphate buffer containing glucose and albumin at 37° C, using a Clark type oxygen electrode. The trained rats showed less body weight gain during the experiment. The weights of BAT and epididymal white adipose tissue were smaller in the trained rats. Noradrenaline- and glucagon-stimulated oxygen consumption were also significantly smaller in the trained rats. The tissue DNA level was greater in the trained rats, but the DNA content per tissue pad did not significantly differ. The results indicate that running training reduces BAT thermogenesis, possibly as an adaptation to conserve energy substrates for physical work.     

Effects of high fat diets on hibernation and adipose tissue in Turkish hamsters

Summary The effects of dietary fat saturation and fat content on hibernation and several properties of white and brown adipose tissue (WAT and BAT, respectively) were investigated in Turkish hamsters (Mesocricetus brandti). Male hamsters were housed in a long photoperiod (LD 16:8) at 23°C and fed one of three diets: (1) chow (6.5% fat per weight), (2) chow+13.5% vegetable oil (OIL, 20% fat per weight [largely unsaturated fat]) and (3) chow+13.5% vegetable shortening [SHORTENING, 20% fat per weight (largely saturated fat)]. Five weeks later body weights had stabilized and the animals were transferred to a short photoperiod (LD 8:16) at 3°C. At the peak of the hibernation season (17 weeks) the animals were sacrificed within 24 h of arousal. Chow-fed hamsters had the greatest percentage of animals hibernating and days found torpid compared with the two fat-fed groups, with no differences found between the latter two groups for these measures. There were no differences between hibernating (HIB) and nonhibernating (NON-HIB) hamsters across or within the diet groups for any of the BAT measures [uncoupling protein content, mitochondrial mass, lipoprotein lipase (LPL) activity, and in vivo lipogenesis], nor were there significant effects of the diet on these measures. CHOW-and OIL-fed HIB hamsters showed decreases in body weight. All HIB groups had decreases in each carcass component, several fat pad weights, testes weight, and food intake. No consistent differences in WAT LPL activity or in vivo lipogenesis were found between HIB and NON-HIB hamsters. Feeding saturated high fat diets inhibits hibernation in some species; however, in the present experiment, feeding of both saturated and unsaturated fat-laden diets inhibited hibernation to a similar degree.Abbreviations BAT brown adipose tissue - COA cytochrome-c oxidase - DS dorsal subcutaneus - DSWAT dorsal subcutaneous white adipose tissue - E epididymal - EWAT epididymal white adipose tissue - FFDM fat-free dry mass - HIB hibernating - I interscapular - IBAT intercapsular brown adipose tissue - IS inguinal subeutaneus - ISWAT inguinal subcutaneous white adipose tissue - LPL lipoprotein lipase - NON-HIB non-hibernating - R retroperitoneal - RWAT retroperitoneal white adipose tissue - SDS sodium dodecyl sul - UCP uncoupling protein - WAT white adipose tissue     

Evaluation of physical fitness from field tests at high altitude in circumpubertal boys: comparison with laboratory data

Field tests of running and laboratory tests were performed in La Paz [high altitude (HA), 3700 m] and in Clermont-Ferrand [low altitude (LA), 300 m] to investigate their validity at HA. Prepubertal boys of mean ages 10.6 years (HA1,n = 16; LA1,n = 28) and pubertal boys of 13.7 years (HA2,n = 12; LA2,n = 41) took part in the study. All the boys performed a 30-m sprint (v _30m), a 30-s shuttle run (v _3os) and a progressive shuttle run test until their maximal aerobic velocity (v _maxsRT). Maximal oxygen consumption was extrapolated from the last test. . In the laboratory, the boys performed a force-velocity test (P _max), a Wingate test (P _Wing) and a graded test to measure maximal oxygen consumption ; direct method) on a cycle ergometer. At similar ages, there was no significant difference between HA and LA boys forv _30m andP _max. Thev _30s of HA boys was 3%–4% lower than those of LA boys (P<0.05); there was no significant difference forP _Wing. Significant relationships were observed at both altitudes betweenP _max (watts per kilogram) andv _30m (HA:r=0.76; LA:r=0.84) and betweenP _Wing andv _30s (HA:r=0.67; LA:r = 0.77); the slopes and the origins were the same at HA and LA. The ,v _maxSRT and were lower by 9%, 12% and 20%, respectively, at HA than at LA (P<0.05). However, the relationships between and (litres per minute) at HA (r=0.88) and at LA (r=0.93) were identical. In conclusion, chronic hypoxia did not modify performance in very short dash exercises. The influence of HA appeared when the exercise duration increased and, during a maximal shuttle run test, performance was reduced by 10% at HA. Moreover, it was possible to assessP _max,P _Wing and at HA as well as at LA from field tests.     

Changes in structure and function of the human left ventricle after acclimatization to high altitude

To analyse the role of changes in structure and function of the left ventricle in determining cardiac function at rest and during exercise, several two-dimensional and Doppler echocardiographic measurements were performed on 11 healthy subjects immediately before an Himalayan expedition (Nun, 7135 m), during acclimatization (3 weeks) and 14 days after the return. At rest decreases were found in cardiac index (CI) (3.23 l.min-1.m-2, SD 0.4 vs 3.82 l.min-1.m-2, SD 0.58, P less than 0.01), left ventricular mass (55.3 g.m-2, SD 9.4 vs 65.2 g.m-2, SD 13.5, P less than 0.005) and left ventricular end-diastolic volume (LVEDV) (53.9 ml.m-2, SD 6.9 vs 64.8 ml.m-2, SD 9.1, P less than 0.001) after acclimatization; by contrast the coefficient of peak arterial pressure to left ventricular end-systolic volume (PAP/ESV) (7.8, SD 1.6 vs 6.0, SD 1.8, P less than 0.005) and mean wall stress [286 kdyn.cm-2, SD 31 vs 250 kdyn.cm-2, SD 21 (2.86 N.cm-2, SD 0.31 vs 2.50 N.cm-2, SD 0.21), P less than 0.005] increased. After return to sea level, low values of CI and mass persisted despite a return to normal of LVEDV and preload. A reduction of PAP/ESV was also observed. At peak exercise, PAP/ESV (8.7, SD 2.4 vs 12.8, SD 2.0, P less than 0.0025), CI (9.8 l.min-1.m-2, SD 2.5 vs 11.6 l.min-1.m-2, SD 1.6, P less than 0.05) and the ejection fraction (69%, SD 6 vs 76%, SD 4, P less than 0.05) were lower after return to sea level than before departure.(ABSTRACT TRUNCATED AT 250 WORDS)     

Secular change in growth of native children and adolescents at high altitude I. Puno,Peru (3800 meters)

A cross sectional sample of 969 native males from Puno (Peru), altitude 3800 m, ranging in age from 7–20 years, and studied for body height, weight, sitting height, leg length, and chest circumference in 1980, were compared, from the point of view of secular trend, with another cross sectional sample of 992 native males from the same place, which were investigated in 1945. In addition, similar observations were carried out in 1980, in a group of 112 females. The data indicate that in Puno there has been no secular increment in the adult body size. However for all ages between 7 and 19 years, body weight and height were significantly greater in 1980 than in 1945. This may be due to earlier sexual maturation in the present generation.     

Brown adipose tissue: Updates in cellular and molecular biology

Brown adipose tissue (BAT) is mainly composed of adipocytes, it is highly vascularized and innervated, and can be activated in adult humans. Brown adipocytes are responsible for performing non-shivering thermogenesis, which is exclusively mediated by uncoupling protein (UCP) -1 (a protein found in the inner mitochondrial membrane), the hallmark of BAT, responsible for the uncoupling of the proton leakage from the ATP production, therefore, generating heat (i.e. thermogenesis). Besides UCP1, other compounds are essential not only to thermogenesis, but also to the proliferation and differentiation of BAT, including peroxisome proliferator-activated receptor (PPAR) family, PPARgamma coactivator 1 (PGC1)-alpha, and PRD1-BF-1-RIZ1 homologous domain protein containing protein (PRDM) -16. The sympathetic nervous system centrally regulates thermogenesis through norepinephrine, which acts on the adrenergic receptors of BAT. This bound leads to the initialization of the many pathways that may activate thermogenesis in acute and/or chronic ways. In summary, this mini-review aims to demonstrate the latest advances in the knowledge of BAT.     

Growth of lowland native children of European Ancestry during sojourn at high altitude (3,200 m)

The moderate growth retardation frequently observed among children living at high altitude is usually assumed to result from hypoxic stress. However, such children are frequently from the poorer socioeconomic strata of their societies and may suffer malnutrition, poor hygiene, inadequate medical care, and overcrowding—factors also associated with growth retardation. The objective of this study was to determine if there is a statistically observable alteration in the growth of middle-class children of European ancestry during sojourn at high altitude. Semilongitudinal height/weight measurements were gathered retrospectively from medical records of 18 boys and 17 girls who were born at low altitude, were well-nourished and clinically normal, and who had lived at Achoma, Peru (altitude 3,200 m), continuously for 9–36 months. Measurements were divided, by sex, into four cohorts: I (3–6 months at Achoma), II (6–12 months), III (12–18 months), and IV (18–24 months); initial, presojourn, height and weight were also obtained. All heights and weights were normalized with age-specific reference values. Changes in Z scores (ΔZ) during sojourn were calculated for each subject by subtracting the score of the presojourn value from those of cohorts I–IV. Paired t-tests revealed, among the boys, a significant decline in Z score for weight during sojourn in all four cohorts. Weight scores for the girls also declined in all four cohorts, although only the change in cohort III was significant. Height scores showed a decline with time at sojourn in the boys, but in girls there is an initial drop followed by a steady increase to presojourn levels. These results are consistent with the view that moderate hypoxia exerts a primary growth-limiting effect even on healthy, well-nourished children.     

Brown adipose tissue functions in humans

Human adults have functionally active BAT. The metabolic function can be reliably measured in vivo using modern imaging modalities (namely PET/CT). Cold seems to be one of the most potent stimulators of BAT metabolic activity but other stimulators (for example insulin) are actively studied. Obesity is related to lower metabolic activity of BAT but it may be reversed after successful weight reduction such as after bariatric surgery. This article is part of a Special Issue entitled Brown and White Fat: From Signaling to Disease.