Replication of SARS-CoV-2 in adipose tissue determines organ and systemic lipid metabolism in hamsters and humans.
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ABSTRACT:
SUBMITTER: Zickler M
PROVIDER: S-EPMC8663969 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Recent studies suggest that brown adipose tissue (BAT) plays a role in energy and glucose metabolism in humans. However, the physiological significance of human BAT in lipid metabolism remains unknown. We studied 16 overweight/obese men during prolonged, non-shivering cold and thermoneutral conditions using stable isotopic tracer methodologies in conjunction with hyperinsulinemic-euglycemic clamps and BAT and white adipose tissue (WAT) biopsies. BAT volume was significantly associated with increased whole-body lipolysis, triglyceride-free fatty acid (FFA) cycling, FFA oxidation, and adipose tissue insulin sensitivity. Functional analysis of BAT and WAT demonstrated the greater thermogenic capacity of BAT compared to WAT, while molecular analysis revealed a cold-induced upregulation of genes involved in lipid metabolism only in BAT. The accelerated mobilization and oxidation of lipids upon BAT activation supports a putative role for BAT in the regulation of lipid metabolism in humans.
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Project description:Dysregulation of lipid metabolism in individual tissues leads to systemic disruption of insulin action and glucose metabolism. Utilizing quantitative lipidomic analyses and mice deficient in adipose tissue lipid chaperones aP2 and mal1, we explored how metabolic alterations in adipose tissue are linked to whole-body metabolism through lipid signals. A robust increase in de novo lipogenesis rendered the adipose tissue of these mice resistant to the deleterious effects of dietary lipid exposure. Systemic lipid profiling also led to identification of C16:1n7-palmitoleate as an adipose tissue-derived lipid hormone that strongly stimulates muscle insulin action and suppresses hepatosteatosis. Our data reveal a lipid-mediated endocrine network and demonstrate that adipose tissue uses lipokines such as C16:1n7-palmitoleate to communicate with distant organs and regulate systemic metabolic homeostasis.
| S-EPMC2728618 | biostudies-literature
Project description:The circadian clock is a cell-autonomous transcription-translation feedback mechanism that anticipates and adapts physiology and behavior to different phases of the day. A variety of factors including hormones, temperature, food-intake, and exercise can act on tissue-specific peripheral clocks to alter the expression of genes that influence metabolism, all in a time-of-day dependent manner. The aim of this study was to elucidate the effects of exercise timing on adipose tissue metabolism. We performed RNA sequencing on inguinal adipose tissue of mice immediately following maximal exercise or sham treatment at the early rest or early active phase. Only during the early active phase did exercise elicit an immediate increase in serum nonesterified fatty acids. Furthermore, early active phase exercise increased expression of markers of thermogenesis and mitochondrial proliferation in inguinal adipose tissue. In vitro, synchronized 3T3-L1 adipocytes showed a timing-dependent difference in Adrb2 expression, as well as a greater lipolytic activity. Thus, the response of adipose tissue to exercise is time-of-day sensitive and may be partly driven by the circadian clock. To determine the influence of feeding state on the time-of-day response to exercise, we replicated the experiment in 10-h-fasted early rest phase mice to mimic the early active phase metabolic status. A 10-h fast led to a similar lipolytic response as observed after active phase exercise but did not replicate the transcriptomic response, suggesting that the observed changes in gene expression are not driven by feeding status. In conclusion, acute exercise elicits timing-specific effects on adipose tissue to maintain metabolic homeostasis.
| S-EPMC9974500 | biostudies-literature
Project description:Hamsters have been long accepted as animal models to study the lipid metabolism in humans. However, very few scientific works described in detail the fatty acid (FA) composition of plasma and erythrocytes in hamsters in relation to their dietary intake, and none work was found comparing them with that described in humans. Therefore, a study was carried out to compare the effect of ingesting olive oil or dairy fat, as part of an equilibrated diet in healthy subjects, on plasma and erythrocytes FA composition. More than 40 FA were detected in samples of both species. It was demonstrated that plasma total FA (TFA) concentration and FA profiles are similar in humans and hamsters. In both species linoleic, oleic and palmitic acids are the main FA and accounted for the 70% of TFA. Differences found between species can be explained by differences in the dietary intake and differences in the proportion of triglycerides, cholesteryl esters and phospholipid fractions in plasma of both species. Changes in dietary FA intake causes similar changes in FA concentration in the plasma of both species and can be explained by the same metabolic processes. The erythrocyte FA profile differs more between the two species. Moreover, unlike humans, the FA profile of hamster erythrocytes is more sensitive to changes in dietary FA than that of plasma.
| S-EPMC8991696 | biostudies-literature
Project description:Aims/hypothesisAcetyl coenzyme A acetyltransferase (ACAT), also known as acetoacetyl-CoA thiolase, catalyses the formation of acetoacetyl-CoA from acetyl-CoA and forms part of the isoprenoid biosynthesis pathway. Thus, ACAT plays a central role in cholesterol metabolism in a variety of cells. Here, we aimed to assess the effect of hepatic Acat2 overexpression on cholesterol metabolism and systemic energy metabolism.MethodsWe generated liver-targeted adeno-associated virus 9 (AAV9) to achieve hepatic Acat2 overexpression in mice. Mice were injected with AAV9 through the tail vein and subjected to morphological, physiological (body composition, indirect calorimetry, treadmill, GTT, blood biochemistry, cardiac ultrasonography and ECG), histochemical, gene expression and metabolomic analysis under normal diet or feeding with high-fat diet to investigate the role of ACAT2 in the liver.ResultsHepatic Acat2 overexpression reduced body weight and total fat mass, elevated the metabolic rate, improved glucose tolerance and lowered the serum cholesterol level of mice. In addition, the overexpression of Acat2 inhibited fatty acid, glucose and ketone metabolic pathways but promoted cholesterol metabolism and changed the bile acid pool and composition of the liver. Hepatic Acat2 overexpression also decreased the size of white adipocytes and promoted lipid metabolism in white adipose tissue. Furthermore, hepatic Acat2 overexpression protected mice from high-fat-diet-induced weight gain and metabolic defects CONCLUSIONS/INTERPRETATION: Our study identifies an essential role for ACAT2 in cholesterol metabolism and systemic energy expenditure and provides key insights into the metabolic benefits of hepatic Acat2 overexpression. Thus, adenoviral Acat2 overexpression in the liver may be a potential therapeutic tool in the treatment of obesity and hypercholesterolaemia.
| S-EPMC9665029 | biostudies-literature
Project description:Brown adipose tissue (BAT) is a central organ that acts to increase energy expenditure; its regulatory factors could be clinically useful in the treatment of obesity. Tetrahydrobiopterin (BH4) is an essential cofactor of tyrosine hydroxylase and nitric oxide synthase (NOS). Although BH4 regulates the known regulatory factors of BAT, such as noradrenaline (NA) and NO, participation of BH4 in BAT function remains unclear. In the present study, we investigate the role of BH4 in the regulation of BAT. Hph-1 mice, a mouse model of BH4 deficiency, exhibit obesity, adiposity, glucose intolerance, insulin resistance, and impaired BAT function. Impaired BAT function was ameliorated together with systemic metabolic disturbances by BAT transplantation from BH4-sufficient mice (control mice) into BH4-deficient mice, strongly suggesting that BH4-induced BAT has a critical role in the regulation of systemic energy metabolism. Both NA derived from the sympathetic nerve and NO derived from endothelial NOS in the blood vessels participate in the regulation of BH4. In addition, a direct effect of BH4 in the stimulation of brown adipocytes via NO is implicated. Taken together, BH4 activates BAT and regulates systemic energy metabolism; this suggests an approach for metabolic disorders, such as obesity and diabetes.
| S-EPMC5414566 | biostudies-literature
Project description:Background. Naturally occurring substances from the flavanol and anthocyanin family of polyphenols have been proposed to exert beneficial effects in the course of obesity. We hypothesized that their effects on attenuating obesity-induced dyslipidemia as well as the associated inflammatory sequelae especially have health-promoting potential. Methods. Male C57BL/6J mice (n = 52) received a control low-fat diet (LFD; 10?kcal% fat) for 6 weeks followed by 24 weeks of either LFD (n = 13) or high-fat diet (HFD; 45?kcal% fat; n = 13) or HFD supplemented with 0.1% w/w of the flavanol compound epicatechin (HFD+E; n = 13) or an anthocyanin-rich bilberry extract (HFD+B; n = 13). Energy substrate utilization was determined by indirect calorimetry in a subset of mice following the dietary switch and at the end of the experiment. Blood samples were collected at baseline and at 3 days and 4, 12, and 20 weeks after dietary switch and analyzed for systemic lipids and proinflammatory cytokines. Adipose tissue (AT) histopathology and inflammatory gene expression as well as hepatic lipid content were analyzed after sacrifice. Results. The switch from a LFD to a HFD lowered the respiratory exchange ratio and increased plasma cholesterol and hepatic lipid content. These changes were not attenuated by HFD+E or HFD+B. Furthermore, the polyphenol compounds could not prevent HFD-induced systemic rise of TNF-? levels. Interestingly, a significant reduction in Tnf gene expression in HFD+B mice was observed in the AT. Furthermore, HFD+B, but not HFD+E, significantly prevented the early upregulation of circulating neutrophil chemoattractant mKC. However, no differences in AT histopathology were observed between the HFD types. Conclusion. Supplementation of HFD with an anthocyanin-rich bilberry extract but not with the flavanol epicatechin may exert beneficial effects on the systemic early inflammatory response associated with diet-induced obesity. These systemic effects were transient and not observed after prolongation of HFD-feeding (24 weeks). On the tissue level, long-term treatment with bilberry attenuated TNF-? expression in adipose tissue.
| S-EPMC4913062 | biostudies-literature
Project description:The prevalence of obesity and type 2 diabetes is increasing worldwide and threatens to shorten lifespan. Impaired insulin action in peripheral tissues is a major pathogenic factor. Insulin stimulates glucose uptake in adipose tissue through the GLUT4 (also known as SLC2A4) glucose transporter, and alterations in adipose tissue GLUT4 expression or function regulate systemic insulin sensitivity. Downregulation of human and mouse adipose tissue GLUT4 occurs early in diabetes development. Here we report that adipose tissue GLUT4 regulates the expression of carbohydrate-responsive-element-binding protein (ChREBP; also known as MLXIPL), a transcriptional regulator of lipogenic and glycolytic genes. Furthermore, adipose ChREBP is a major determinant of adipose tissue fatty acid synthesis and systemic insulin sensitivity. We find a new mechanism for glucose regulation of ChREBP: glucose-mediated activation of the canonical ChREBP isoform (ChREBP-?) induces expression of a novel, potent isoform (ChREBP-?) that is transcribed from an alternative promoter. ChREBP-? expression in human adipose tissue predicts insulin sensitivity, indicating that it may be an effective target for treating diabetes.
| S-EPMC3341994 | biostudies-literature
Project description:The protective effects of lower body subcutaneous adiposity are linked to the depot functioning as a "metabolic sink" receiving and sequestering excess lipid. This postulate, however, is based on indirect evidence. Mechanisms that mediate this protection are unknown. Here we directly examined this with progressive subcutaneous adipose tissue removal. Ad libitum chow fed mice underwent sham surgery, unilateral or bilateral removal of inguinal adipose tissue or bilateral removal of both inguinal and dorsal adipose tissue. Subsequently mice were separated into 5 week chow or 5 or 13 week HFD groups (N = 10 per group). Primary outcome measures included adipocyte distribution, muscle and liver triglycerides, glucose tolerance, circulating adipocytokines and muscle insulin sensitivity. Subcutaneous adipose tissue removal caused lipid accumulation in femoral muscle proximal to excision, however, lipid accumulation was not proportionally inverse to adipose tissue quantity excised. Accumulative adipose removal was associated with an incremental reduction in systemic glucose tolerance in 13 week HFD mice. Although insulin-stimulated pAkt/Akt did not progressively decrease among surgery groups following 13 weeks of HFD, there was a suppressed pAkt/Akt response in the non-insulin stimulated (saline-injected) 13 week HFD mice. Hence, increases in lower body subcutaneous adipose removal resulted in incremental decreases in the effectiveness of basal insulin sensitivity of femoral muscle. The current data supports that the subcutaneous depot protects systemic glucose homeostasis while also protecting proximal muscle from metabolic dysregulation and lipid accumulation. Removal of the "metabolic sink" likely leads to glucose intolerance because of decreased storage space for glucose and/or lipids.
| S-EPMC6768251 | biostudies-literature
Project description:ObjectiveAging is accompanied by loss of brown adipocytes and a decline in their thermogenic potential, which may exacerbate the development of adiposity and other metabolic disorders. Presently, only limited evidence exists describing the molecular alterations leading to impaired brown adipogenesis with aging and the contribution of these processes to changes of systemic energy metabolism.MethodsSamples of young and aged murine brown and white adipose tissue were used to compare age-related changes of brown adipogenic gene expression and thermogenesis-related lipid mobilization. To identify potential markers of brown adipose tissue aging, non-targeted proteomic and metabolomic as well as targeted lipid analyses were conducted on young and aged tissue samples. Subsequently, the effects of several candidate lipid classes on brown adipocyte function were examined.ResultsCorroborating previous reports of reduced expression of uncoupling protein-1, we observe impaired signaling required for lipid mobilization in aged brown fat after adrenergic stimulation. Omics analyses additionally confirm the age-related impairment of lipid homeostasis and reveal the accumulation of specific lipid classes, including certain sphingolipids, ceramides, and dolichols in aged brown fat. While ceramides as well as enzymes of dolichol metabolism inhibit brown adipogenesis, inhibition of sphingosine 1-phosphate receptor 2 induces brown adipocyte differentiation.ConclusionsOur functional analyses show that changes in specific lipid species, as observed during aging, may contribute to reduced thermogenic potential. They thus uncover potential biomarkers of aging as well as molecular mechanisms that could contribute to the degradation of brown adipocytes, thereby providing potential treatment strategies of age-related metabolic conditions.
| S-EPMC6531832 | biostudies-literature