scholarly journals Accelerated developmental adipogenesis programs adipose tissue dysfunction and cardiometabolic risk in offspring born to dams with metabolic dysfunction

2021 ◽  
Author(s):  
Anna Mikolajczak ◽  
Nada A Sallam ◽  
Radha D Singh ◽  
Taylor B Scheidl ◽  
Emma J. Walsh ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Fat Mass ◽  
Cardiometabolic Risk ◽  
Late Gestation ◽  
Whole Body ◽  
Distribution Analysis ◽  
Metabolic Dysfunction ◽  
Wild Type ◽  
Cell Size Distribution ◽  
Differentiation Potential

This study determined if a perturbation in in utero adipogenesis leading to later-life adipose tissue (AT) dysfunction underlies programming of cardiometabolic risk in offspring born to dams with metabolic dysfunction. Female mice heterozygous for the leptin receptor deficiency (Hetdb) had 2.4-fold higher pre-pregnancy fat mass and in late gestation had higher plasma insulin and triglycerides, compared to wild-type (Wt) females (p < 0.05). To isolate the role of the intrauterine milieu, wild-type (Wt) offspring from each pregnancy were studied. Differentiation potential in isolated progenitors and cell size distribution analysis revealed accelerated adipogenesis in Wt pups born to Hetdb dams, accompanied by a higher accumulation of neonatal fat mass. In adulthood, whole-body fat mass by NMR was higher in male (69%) and female (20%) Wt offspring born to Hetdb vs. Wt pregnancies, along with adipocyte hypertrophy and hyperlipidemia (all p < 0.05). Lipidomic analyses by gas chromatography revealed an increased lipogenic index (16:0/18:2n6) after high fat/fructose diet (HFFD). Postprandial insulin, ADIPO-IR and ex vivo AT lipolytic responses to isoproterenol, were all higher in Wt offspring born to Hetdb dams (p < 0.05). Intrauterine metabolic stimuli may direct a greater proportion of progenitors toward terminal differentiation, thereby predisposing to hypertrophy-induced adipocyte dysfunction.

CTRP6 rapidly responds to acute nutritional changes, regulating adipose tissue expansion and inflammation in mice

2021 ◽  
Author(s):  
Rotem Lahav ◽  
Yulia Haim ◽  
Nikhil Suresh Bhandarkar ◽  
Liron Levin ◽  
Vered Chalifa-Caspi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Tissue Expansion ◽  
Whole Body ◽  
Metabolic Dysfunction ◽  
Wild Type ◽  
High Fat ◽  
Tnf Α ◽  
Fat Feeding ◽  
Nutritional Changes

In chronic obesity, activated adipose tissue pro-inflammatory cascades are tightly linked to metabolic dysfunction. Yet, close temporal analyses of the responses to obesogenic environment such as high-fat feeding (HFF) in susceptible mouse strains question the causal relationship between inflammation and metabolic dysfunction, and/or raises the possibility that certain inflammatory cascades play adaptive/homeostatic, rather than pathogenic roles. Here we hypothesized that CTRP6, a C1QTNF family member, may constitute an early responder to acute nutritional changes in adipose tissue, with potential physiological roles. Both 3 days high-fat feeding (3dHFF) and acute obesity reversal (2 weeks switch to low-fat diet after 8w-HFF) already induced marked changes in whole-body fuel utilization. While adipose tissue expression of classical pro-inflammatory cytokines (Tnf-α, Ccl2, Il1b) exhibited no, or only minor, change, C1qtnf6 uniquely increased, and decreased, in response to 3dHFF and acute obesity reversal, respectively. CTRP6 knockout (KO) mouse embryonic fibroblasts (MEF) exhibited increased adipogenic gene expression (Pparg, Fabp4, Adipoq) and markedly reduced inflammatory genes (Tnf-α, Ccl2, Il6) compared to wild-type MEF, and recombinant CTRP6 induced the opposite gene expression signature, as assessed by RNA-sequencing. Consistently, 3dHFF of CTRP6-KO mice induced a greater whole-body and adipose tissue weight gain compared to wild-type littermates. Collectively, we propose CTRP6 as a gene that rapidly responds to acute changes in caloric intake, acting in acute over-nutrition to induce a "physiological inflammatory response" that limits adipose tissue expansion.

scholarly journals Developmental aspects of adipose tissue in GH receptor and prolactin receptor gene disrupted mice: site-specific effects upon proliferation, differentiation and hormone sensitivity

2006 ◽  
Vol 191 (1) ◽  
pp. 101-111 ◽  
Author(s):  
David J Flint ◽  
Nadine Binart ◽  
Stephanie Boumard ◽  
John J Kopchick ◽  
Paul Kelly
Keyword(s):  
Adipose Tissue ◽  
Receptor Gene ◽  
Metabolic Effects ◽  
Wild Type ◽  
Extrinsic Factors ◽  
Differentiation Potential ◽  
Site Specific ◽  
Proliferation And Differentiation

Direct metabolic effects of GH on adipose tissue are well established, but effects of prolactin (PRL) have been more controversial. Recent studies have demonstrated PRL receptors on adipocytes and effects of PRL on adipose tissue in vitro. The role of GH in adipocyte proliferation and differentiation is also controversial, since GH stimulates adipocyte differentiation in cell lines, whereas it stimulates proliferation but inhibits differentiation of adipocytes in primary cell culture. Using female gene disrupted (ko) mice, we showed that absence of PRL receptors (PRLRko) impaired development of both internal and s.c. adipose tissue, due to reduced numbers of adipocytes, an effect differing from that of reduced food intake, where cell volume is decreased. In contrast, GHRko mice exhibited major decreases in the number of internal adipocytes, whereas s.c. adipocyte numbers were increased, even though body weight was decreased by 40–50%. The changes in adipose tissue in PRLRko mice appeared to be entirely due to extrinsic factors since preadipocytes proliferated and differentiated in similar fashion to wild-type animals in vitro and their response to insulin and isoproterenol was similar to wild-type animals. This contrasted with GHRko mice, where s.c. adipocytes proliferated, differentiated, and responded to hormones in identical fashion to controls, whereas parametrial adipocytes exhibited markedly depressed proliferation and differentiation potential and failed to respond to insulin or noradrenaline. Our results provide in vivo evidence that both GH and PRL stimulate differentiation of adipocytes but that the effects of GH are site specific and induce intrinsic changes in the precursor population, which are retained in vitro.

scholarly journals The androgen receptor in bone marrow progenitor cells negatively regulates fat mass

2018 ◽  
Vol 237 (1) ◽  
pp. 15-27 ◽  
Author(s):  
Patricia K Russell ◽  
Salvatore Mangiafico ◽  
Barbara C Fam ◽  
Michele V Clarke ◽  
Evelyn S Marin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Adipose Tissue ◽  
Androgen Receptor ◽  
Progenitor Cells ◽  
Fat Mass ◽  
Elevated Serum ◽  
Gene Replacement ◽  
Whole Body ◽  
Clinical Aspects ◽  
Mesenchymal Progenitor Cells

It is well established that testosterone negatively regulates fat mass in humans and mice; however, the mechanism by which testosterone exerts these effects is poorly understood. We and others have shown that deletion of the androgen receptor (AR) in male mice results in a phenotype that mimics the three key clinical aspects of hypogonadism in human males; increased fat mass and decreased bone and muscle mass. We now show that replacement of the Ar gene specifically in mesenchymal progenitor cells (PCs) residing in the bone marrow of Global-ARKO mice, in the absence of the AR in all other tissues (PC-AR Gene Replacements), completely attenuates their increased fat accumulation. Inguinal subcutaneous white adipose tissue and intra-abdominal retroperitoneal visceral adipose tissue depots in PC-AR Gene Replacement mice were 50–80% lower than wild-type (WT) and 75–90% lower than Global-ARKO controls at 12 weeks of age. The marked decrease in subcutaneous and visceral fat mass in PC-AR Gene Replacements was associated with an increase in the number of small adipocytes and a healthier metabolic profile compared to WT controls, characterised by normal serum leptin and elevated serum adiponectin levels. Euglycaemic/hyperinsulinaemic clamp studies reveal that the PC-AR Gene Replacement mice have improved whole-body insulin sensitivity with higher glucose infusion rates compared to WT mice and increased glucose uptake into subcutaneous and intra-abdominal fat. In conclusion, these data provide the first evidence for an action of androgens via the AR in mesenchymal bone marrow PCs to negatively regulate fat mass and improve metabolic function.

scholarly journals Effects of isoenergetic overfeeding of either carbohydrate or fat in young men

2000 ◽  
Vol 84 (2) ◽  
pp. 233-245 ◽  
Author(s):  
Ole Lammert ◽  
Niels Grunnet ◽  
Peter Faber ◽  
Kirsten Schroll Bjørnsbo ◽  
John Dich ◽  
...  
Keyword(s):  
Fat Mass ◽  
De Novo ◽  
Fat Free Mass ◽  
Whole Body ◽  
Distribution Analysis ◽  
Mass Isotopomer Distribution Analysis ◽  
The Difference ◽  
Normal Men ◽  
Plasma Leptin ◽  
Mass Increase

Ten pairs of normal men were overfed by 5 MJ/d for 21 d with either a carbohydrate-rich or a fat-rich diet (C- and F-group). The two subjects in each pair were requested to follow each other throughout the day to ensure similar physical activity and were otherwise allowed to maintain normal daily life. The increase in body weight, fat free mass and fat mass showed great variation, the mean increases being 1·5 kg, 0·6 kg and 0·9 kg respectively. No significant differences between the C- and F-group were observed. Heat production during sleep did not change during overfeeding. The RQ during sleep was 0·86 and 0·78 in the C- and F-group respectively. The accumulated faecal loss of energy, DM, carbohydrate and protein was significantly higher in the C- compared with the F-group (30, 44, 69 and 51 % higher respectively), whereas the fat loss was the same in the two groups. N balance was not different between the C- and F-group and was positive. Fractional contribution from hepatic de novo lipogenesis, as measured by mass isotopomer distribution analysis after administration of [1-13C]acetate, was 0·20 and 0·03 in the C-group and the F-group respectively. Absolute hepatic de novo lipogenesis in the C-group was on average 211 g per 21 d. Whole-body de novo lipogenesis, as obtained by the difference between fat mass increase and dietary fat available for storage, was positive in six of the ten subjects in the C-group (mean 332 (SEM 191) g per 21 d). The change in plasma leptin concentration was positively correlated with the change in fat mass. Thus, fat storage during overfeeding of isoenergetic amounts of diets rich in carbohydrate or in fat was not significantly different, and carbohydrates seemed to be converted to fat by both hepatic and extrahepatic lipogenesis.

scholarly journals Sex differences in pericardial adipose tissue assessed by PET/CT and association with cardiometabolic risk

2018 ◽  
Vol 59 (10) ◽  
pp. 1203-1209 ◽  
Author(s):  
Corey M Gill ◽  
Debora C Azevedo ◽  
Adriana L Oliveira ◽  
Edgar L Martinez-Salazar ◽  
Martin Torriani ◽  
...  
Keyword(s):  
Sex Differences ◽  
Adipose Tissue ◽  
Operating Characteristic ◽  
Cardiometabolic Risk ◽  
Whole Body ◽  
The Metabolic Syndrome ◽  
Body Adiposity ◽  
Positron Emission ◽  
Pericardial Adipose Tissue ◽  
Pet Ct

Background Recent studies suggest that pericardial adipose tissue (PAT) is associated with whole body adiposity and insulin resistance. Moreover, the incidence of cardiovascular disease (CVD) differs between men and women. Although CVD is more prevalent in men, women suffering from CVD have a higher mortality compared to men. Differences in PAT may account for some of the observed sex differences in manifestations of CVD. Purpose To assess pericardial adipose tissue (PAT) as a biomarker for cardiometabolic risk and to assess potential sex differences. Material and Methods We studied 303 individuals (151 women, 152 men; mean age = 57 ± 17 years) across the weight spectrum. PAT and abdominal adipose tissue were quantified using clinical computed tomography (CT) scans obtained as part of a positron emission tomography (PET)/CT. Cardiometabolic risk factors were assessed from medical records. Linear regression and receiver operating characteristic (ROC) curve analyses were performed to evaluate associations between PAT and cardiometabolic risk. Results PAT was higher in overweight and obese individuals compared to lean individuals and higher in men compared to women. PAT was positively associated with body mass index, abdominal fat ( P < 0.0001), fasting glucose, and serum lipids ( P < 0.05) with stronger associations in women than in men. PAT was accurate in detecting the prevalence of the metabolic syndrome with 74% sensitivity and 76% specificity (AUC = 0.80). Conclusion PAT is associated with measures of cardiometabolic risk and these associations are stronger in women compared to men. PAT could serve as a biomarker for opportunistic screening for cardiometabolic risk in patients undergoing chest CT.

Adipose-specific overexpression of GLUT4 reverses insulin resistance and diabetes in mice lacking GLUT4 selectively in muscle

2005 ◽  
Vol 289 (4) ◽  
pp. E551-E561 ◽  
Author(s):  
Eugenia Carvalho ◽  
Ko Kotani ◽  
Odile D. Peroni ◽  
Barbara B. Kahn
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Glucose Transport ◽  
Fat Mass ◽  
Glucose Transporter ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Whole Body ◽  
Hepatic Glucose ◽  
Clamp Study

Adipose tissue plays an important role in glucose homeostasis and affects insulin sensitivity in other tissues. In obesity and type 2 diabetes, glucose transporter 4 (GLUT4) is downregulated in adipose tissue, and glucose transport is also impaired in muscle. To determine whether overexpression of GLUT4 selectively in adipose tissue could prevent insulin resistance when glucose transport is impaired in muscle, we bred muscle GLUT4 knockout (MG4KO) mice to mice overexpressing GLUT4 in adipose tissue (AG4Tg). Overexpression of GLUT4 in fat not only normalized the fasting hyperglycemia and glucose intolerance in MG4KO mice, but it reduced these parameters to below normal levels. Glucose infusion rate during a euglycemic clamp study was reduced 46% in MG4KO compared with controls and was restored to control levels in AG4Tg-MG4KO. Similarly, insulin action to suppress hepatic glucose production was impaired in MG4KO mice and was restored to control levels in AG4Tg-MG4KO. 2-Deoxyglucose uptake during the clamp was increased approximately twofold in white adipose tissue but remained reduced in skeletal muscle of AG4Tg-MG4KO mice. AG4Tg and AG4Tg-MG4KO mice have a slight increase in fat mass, a twofold elevation in serum free fatty acids, an ∼50% increase in serum leptin, and a 50% decrease in serum adiponectin. In MG4KO mice, serum resistin is increased 34% and GLUT4 overexpression in fat reverses this. Overexpression of GLUT4 in fat also reverses the enhanced clearance of an oral lipid load in MG4KO mice. Thus overexpression of GLUT4 in fat reverses whole body insulin resistance in MG4KO mice without restoring glucose transport in muscle. This effect occurs even though AG4Tg-MG4KO mice have increased fat mass and low adiponectin and is associated with normalization of elevated resistin levels.

Overexpression of Foxf2 in adipose tissue is associated with lower levels of IRS1 and decreased glucose uptake in vivo

2010 ◽  
Vol 298 (3) ◽  
pp. E548-E554 ◽  
Author(s):  
Rickard Westergren ◽  
Daniel Nilsson ◽  
Mikael Heglind ◽  
Zahra Arani ◽  
Mats Grände ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Glucose Tolerance ◽  
Glucose Uptake ◽  
Target Genes ◽  
Whole Body ◽  
Wild Type ◽  
Intravenous Glucose ◽  
Downstream Target ◽  
Protein Levels

Many members of the forkhead genes family of transcription factors have been implicated as important regulators of metabolism, in particular, glucose homeostasis, e.g., Foxo1, Foxa3, and Foxc2. The purpose of this study was to exploit the possibility that yet unknown members of this gene family play a role in regulating glucose tolerance in adipocytes. We identified Foxf2 in a screen for adipose-expressed forkhead genes. In vivo overexpression of Foxf2 in an adipose tissue-restricted fashion demonstrated that such mice display a significantly induced insulin secretion in response to an intravenous glucose load compared with wild-type littermates. In response to increased Foxf2 expression, insulin receptor substrate 1 (IRS1) mRNA and protein levels are significantly downregulated in adipocytes; however, the ratio of serine vs. tyrosine phosphorylation of IRS1 seems to remain unaffected. Furthermore, adipocytes overexpressing Foxf2 have a significantly lower insulin-mediated glucose uptake compared with wild-type adipocytes. These findings argue that Foxf2 is a previously unrecognized regulator of cellular and systemic whole body glucose tolerance, at least in part, due to lower levels of IRS1. Foxf2 and its downstream target genes can provide new insights with regard to identification of novel therapeutic targets.

Effects of the presence, absence, and overexpression of uncoupling protein-3 on adiposity and fuel metabolism in congenic mice

2006 ◽  
Vol 290 (6) ◽  
pp. E1304-E1312 ◽  
Author(s):  
Sheila R. Costford ◽  
Shehla N. Chaudhry ◽  
Mahmoud Salkhordeh ◽  
Mary-Ellen Harper
Keyword(s):  
Adipose Tissue ◽  
Glucose Tolerance ◽  
Uncoupling Protein ◽  
Liver Glycogen ◽  
Whole Body ◽  
Wild Type ◽  
Insulin Tolerance ◽  
Uncoupling Protein 3 ◽  
Brown Adipose ◽  
Inner Membrane Protein

Uncoupling protein-3 (UCP3) is a poorly understood mitochondrial inner membrane protein expressed predominantly in skeletal muscle. The aim of this study was to examine the effects of the absence or constitutive physiological overexpression of UCP3 on whole body energy metabolism, glucose tolerance, and muscle triglyceride content. Congenic male UCP3 knockout mice ( Ucp3 −/−), wild-type, and transgenic UCP3 overexpressing (UCP3Tg) mice were fed a 10% fat diet for 4 or 8 mo after they were weaned. UCP3Tg mice had lower body weights and were less metabolically efficient than wild-type or Ucp3 −/− mice, but they were not hyperphagic. UCP3Tg mice had smaller epididymal white adipose tissue and brown adipose tissue (BAT) depots; however, there were no differences in muscle weights. Glucose and insulin tolerance tests revealed that both UCP3Tg and Ucp3 −/− mice were protected from development of impaired glucose tolerance and were more sensitive to insulin. 2-Deoxy-d-[1-3H]glucose tracer studies showed increased uptake of glucose into BAT and increased storage of liver glycogen in Ucp3 −/− mice. Assessments of intramuscular triglyceride (IMTG) revealed decreases in quadriceps of UCP3Tg mice compared with wild-type and Ucp3 −/− mice. When challenged with a 45% fat diet, Ucp3 −/− mice showed increased accumulation of IMTG compared with wild-type mice, which in turn had greater IMTG than UCP3Tg mice. Results are consistent with a role for UCP3 in preventing accumulation of triglyceride in both adipose tissue and muscle.

scholarly journals Cold tolerance, cold-induced hyperphagia, and nonshivering thermogenesis are normal in α1-AMPK−/− mice

2011 ◽  
Vol 301 (2) ◽  
pp. R473-R483 ◽  
Author(s):  
Jake D. Bauwens ◽  
Eric G. Schmuck ◽  
Christopher R. Lindholm ◽  
Rebecca L. Ertel ◽  
Jacob D. Mulligan ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Cold Exposure ◽  
Whole Body ◽  
Nonshivering Thermogenesis ◽  
Wild Type ◽  
Brown Adipose ◽  
Ampk Activity ◽  
Amp Activated Protein Kinase ◽  
Established Role

Recent studies indicate that a substantial amount of metabolically active brown adipose tissue (BAT) exists in adult humans. Given the unique ability of BAT to convert calories to heat, there is intense interest in understanding the regulation of BAT metabolism in hopes that its manipulation might be an effective way of expending excess calories. Because of the established role of AMP-activated protein kinase (AMPK) as a “metabolic master switch” and its extremely high levels of activity in BAT, it was hypothesized that AMPK might play a central role in regulating BAT metabolism. To test this hypothesis, whole body α1-AMPK−/− (knockout) and wild-type mice were studied 1) under control (room temperature) conditions, 2) during chronic cold exposure (14 days at 4°C), and 3) during acute nonshivering thermogenesis (injection of a β3-adrenergic agonist). Under control conditions, loss of α1-AMPK resulted in downregulation of two important prothermogenic genes in BAT, thyrotropin-releasing hormone (−9.2-fold) and ciliary neurotrophic factor (−8.7-fold). Additionally, it caused significant upregulation of α2-AMPK activity in BAT, white adipose tissue, and liver, but not cardiac or skeletal muscle. During acute nonshivering thermogenesis and chronic cold exposure, body temperature was indistinguishable in the α1-AMPK−/− and wild-type mice. Similarly, the degree of cold-induced hyperphagia was identical in the two groups. We conclude that α1-AMPK does not play an obligatory role in these processes and that adaptations to chronic loss of α1-AMPK are able to compensate for its loss via several mechanisms.

scholarly journals Regulation of Adipose Differentiation by Fructose and GluT5

2012 ◽  
Vol 26 (10) ◽  
pp. 1773-1782 ◽  
Author(s):  
Li Du ◽  
Anthony P. Heaney
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Energy Homeostasis ◽  
Adipocyte Differentiation ◽  
Early Stage ◽  
Whole Body ◽  
Wild Type ◽  
Embryonic Fibroblasts ◽  
Fructose Intake ◽  
Adipose Differentiation

Abstract Adipose tissue is an important metabolic organ that is crucial for whole-body insulin sensitivity and energy homeostasis. Highly refined fructose intake increases visceral adiposity although the mechanism(s) remain unclear. Differentiation of preadipocytes to mature adipocytes is a highly regulated process that is associated with characteristic sequential changes in adipocyte gene expression. We demonstrate that fructose treatment of murine 3T3-L1 cells incubated in standard differentiation medium increases adipogenesis and adipocyte-related gene expression. We further show that the key fructose transporter, GluT5, is expressed in early-stage adipocyte differentiation but is not expressed in mature adipocytes. GluT5 overexpression or knockdown increased and decreased adipocyte differentiation, respectively, and treatment of 3T3-L1 cells with a specific GluT5 inhibitor decreased adipocyte differentiation. Epidymal white adipose tissue was reduced in GluT5−/− mice compared with wild-type mice, and mouse embryonic fibroblasts derived from GluT5−/− mice exhibited impaired adipocyte differentiation. Taken together, these results demonstrate that fructose and GluT5 play an important role in regulating adipose differentiation.

Sign in / Sign up

Export Citation Format

Share Document