Development of VMH obesity: in vivo insulin secretion and tissue insulin sensitivity

1989 ◽  
Vol 257 (2) ◽  
pp. E255-E260 ◽  
Author(s):  
L. Penicaud ◽  
M. F. Kinebanyan ◽  
P. Ferre ◽  
J. Morin ◽  
J. Kande ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Secretion ◽  
White Adipose Tissue ◽  
Glucose Utilization ◽  
Ventromedial Hypothalamus ◽  
Body Fat Mass ◽  
Progressive Development ◽  
Insulin Hypersensitivity

Euglycemic-hyperinsulinemic clamps coupled with an injection of [2-3H]deoxyglucose were performed in rats 1 or 6 wk after lesion of the ventromedial hypothalamus (VMH) and their age-matched controls. In the basal state, glucose utilization was not different in controls and VMH rats in all the tissues studied except in white adipose tissue where it was greatly increased after the lesion. When insulinemia was clamped at 850 microU/ml, glucose utilization was less important in glycolytic and normal in oxidative muscles in animals 1 wk after the lesion (VMH1) compared with controls. In animals 6 wk after the lesion (VMH6), all the muscles utilized less glucose than those of controls. In white adipose tissue, glucose utilization was increased twice more in VMH1 and returned to normal in VMH6. These data demonstrate a progressive development of insulin resistance in muscles. Simultaneously, there is a transient insulin hypersensitivity in white adipose tissue. This, together with a hypersecretion of insulin, could contribute to the development of body fat mass by redirecting glucose towards adipose tissue.

scholarly journals Metabolic consequences of hyperinsulinaemia imposed on normal rats on glucose handling by white adipose tissue, muscles and liver

1990 ◽  
Vol 267 (1) ◽  
pp. 99-103 ◽  
Author(s):  
I Cusin ◽  
J Terrettaz ◽  
F Rohner-Jeanrenaud ◽  
B Jeanrenaud
Keyword(s):  
Adipose Tissue ◽  
White Adipose Tissue ◽  
Glucose Utilization ◽  
Insulin Treatment ◽  
Driving Forces ◽  
Hepatic Glucose Production ◽  
Lipid Synthesis ◽  
Liver Fat ◽  
Insulin Responsiveness

The effects of hyperinsulinaemia imposed on normal rats on the subsequent insulin-responsiveness in vivo of 2-deoxy-D-glucose uptake of white adipose tissue and of various muscle types were investigated. This was done by treating normal rats with insulin via osmotic minipumps, and by comparing them with saline-infused controls. Hyperinsulinaemia produced by prior insulin treatment resulted in a well-tolerated hypoglycaemia. At the end of the treatment, the glucose utilization index of individual tissues was determined by euglycaemic/hyperinsulinaemic clamps associated with the labelled 2-deoxy-D-glucose method. Prior insulin treatment resulted in increased insulin-responsiveness of the glucose utilization index of white adipose tissue, and in increased total lipogenesis in white adipose tissue and fat-pad weight. In contrast, prior insulin treatment resulted in a decreased glucose utilization index of several muscles. These opposite effects of hyperinsulinaemia on glucose utilization in white adipose tissue and muscles persisted when the hypoglycaemia-induced catecholamine output was prevented (adrenomedullectomy, propranolol treatment), as well as when hypoglycaemia was normalized by concomitant insulin treatment and glucose infusion. Insulin suppressed hepatic glucose production during the clamps in insulin-treated rats as in the respective controls, whereas total hepatic lipid synthesis and liver fat content were greater in rats treated with insulin than in controls. It is concluded that hyperinsulinaemia itself could be one of the driving forces responsible for producing increased glucose utilization by white adipose tissue, increased total lipid synthesis with fat accumulation in adipose tissue and the liver, together with an insulin-resistant state at the muscular level.

scholarly journals Hyperinsulinaemia increases insulin action in vivo in white adipose tissue but not in muscles

1990 ◽  
Vol 272 (1) ◽  
pp. 255-257 ◽  
Author(s):  
F Takao ◽  
M C Laury ◽  
A Ktorza ◽  
L Picon ◽  
L Pénicaud
Keyword(s):  
Adipose Tissue ◽  
White Adipose Tissue ◽  
Skeletal Muscles ◽  
Insulin Action ◽  
Glucose Utilization ◽  
Rat Tissues ◽  
Hyperinsulinaemic Clamp ◽  
Euglycaemic Hyperinsulinaemic Clamp

The effect of 4 days of stable hyperglycaemia and resulting hyperinsulinaemia on insulin-induced glucose utilization by individual rat tissues was studied in vivo. The treatment produced a net increase in the glucose utilization index under both basal and insulin-stimulated (euglycaemic/hyperinsulinaemic clamp) conditions in white adipose tissue. On the contrary, glucose utilization was unchanged in aerobic muscles but was decreased in glycolytic skeletal muscles during the clamp.

scholarly journals ADAM19: A Novel Target for Metabolic Syndrome in Humans and Mice

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Lakshini Weerasekera ◽  
Caroline Rudnicka ◽  
Qing-Xiang Sang ◽  
Joanne E. Curran ◽  
Matthew P. Johnson ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Adipose Tissue ◽  
Mouse Model ◽  
White Adipose Tissue ◽  
Mononuclear Cells ◽  
Western World ◽  
Diet Induced Obesity ◽  
The Metabolic Syndrome

Obesity is one of the most prevalent metabolic diseases in the Western world and correlates directly with insulin resistance, which may ultimately culminate in type 2 diabetes (T2D). We sought to ascertain whether the human metalloproteinase A Disintegrin and Metalloproteinase 19 (ADAM19) correlates with parameters of the metabolic syndrome in humans and mice. To determine the potential novel role of ADAM19 in the metabolic syndrome, we first conducted microarray studies on peripheral blood mononuclear cells from a well-characterised human cohort. Secondly, we examined the expression of ADAM19 in liver and gonadal white adipose tissue using an in vivo diet induced obesity mouse model. Finally, we investigated the effect of neutralising ADAM19 on diet induced weight gain, insulin resistance in vivo, and liver TNF-α levels. Significantly, we show that, in humans, ADAM19 strongly correlates with parameters of the metabolic syndrome, particularly BMI, relative fat, HOMA-IR, and triglycerides. Furthermore, we identified that ADAM19 expression was markedly increased in the liver and gonadal white adipose tissue of obese and T2D mice. Excitingly, we demonstrate in our diet induced obesity mouse model that neutralising ADAM19 therapy results in weight loss, improves insulin sensitivity, and reduces liver TNF-α levels. Our novel data suggest that ADAM19 is pro-obesogenic and enhances insulin resistance. Therefore, neutralisation of ADAM19 may be a potential therapeutic approach to treat obesity and T2D.

scholarly journals Lactational metformin exposure programs offspring white adipose tissue glucose homeostasis and resilience to metabolic stress in a sex-dependent manner

2020 ◽  
Vol 318 (5) ◽  
pp. E600-E612 ◽  
Author(s):  
Zach Carlson ◽  
Hannah Hafner ◽  
Molly Mulcahy ◽  
Kaylie Bullock ◽  
Allen Zhu ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Insulin Secretion ◽  
Beta Cell ◽  
Glucose Homeostasis ◽  
White Adipose Tissue ◽  
Female Offspring ◽  
Immunofluorescent Staining ◽  
Beta Cell Proliferation

We previously demonstrated that exposing mouse dams to metformin during gestation results in increased beta-cell mass at birth and increased beta-cell insulin secretion in adult male offspring. Given these favorable changes after a gestational maternal metformin exposure, we wanted to understand the long-term metabolic impact on offspring after exposing dams to metformin during the postnatal window. The newborn period provides a feasible clinical window for intervention and is important for beta-cell proliferation and metabolic tissue development. Using a C57BL/6 model, we administered metformin to dams from the day of birth to postnatal day 21. We monitored maternal health and offspring growth during the lactation window, as well as adult glucose homeostasis through in vivo testing. At necropsy we assessed pancreas and adipocyte morphology using histological and immunofluorescent staining techniques. We found that metformin exposure programmed male and female offspring to be leaner with a higher proportion of small adipocytes in the gonadal white adipose tissue (GWAT). Male, but not female, offspring had an improvement in glucose tolerance as young adults concordant with a mild increase in insulin secretion in response to glucose in vivo. These data demonstrate long-term metabolic programming of offspring associated with maternal exposure to metformin during lactation.

Increased in vivo glucose utilization in 30-day-old obese Zucker rat: role of white adipose tissue

1988 ◽  
Vol 254 (3) ◽  
pp. E342-E348 ◽  
Author(s):  
S. Krief ◽  
R. Bazin ◽  
F. Dupuy ◽  
M. Lavau
Keyword(s):  
Adipose Tissue ◽  
White Adipose Tissue ◽  
Glucose Utilization ◽  
Whole Body ◽  
Glucose Disposal ◽  
Zucker Rats ◽  
Brown Adipose ◽  
Obese Rats ◽  
Proximal Intestine

In vivo whole-body glucose utilization and uptake in multiple individual tissues were investigated in conscious 30-day-old Zucker rats, which when obese are hyperphagic, hyperinsulinemic, and normoglycemic. Whole-body glucose metabolism (assessed by [3-3H]glucose) was 40% higher in obese (fa/fa) than in lean (Fa/fa) rats, suggesting that obese rats were quite responsive to their hyperinsulinemia (140 vs. 55 microU/ml). In obese compared with lean rats, tissue glucose uptake (assessed by the 2-deoxyglucose technique) was increased by 15, 12, and 6 times in dorsal, inguinal, perigonadal white depots, respectively; multiplied by 2.5 in brown adipose tissue; increased by 50% in skin from inguinal region but not in that from cranial, thoracic, or dorsal area; and increased twofold in diaphragm but similar in heart, in proximal intestine, and in total muscular mass of limbs. Our data establish that in young obese rats the hypertrophied white adipose tissue was a major glucose-utilizing tissue whose capacity for glucose disposal compared with that of half the muscular mass. Adipose tissue could therefore play an important role in the homeostasis of glucose in obese rats in the face of their increased carbohydrate intake.

Regional variations in metabolic responses of white adipose tissue to food restriction

1994 ◽  
Vol 267 (6) ◽  
pp. E892-E899 ◽  
Author(s):  
M. C. Sugden ◽  
R. M. Grimshaw ◽  
H. Lall ◽  
M. J. Holness
Keyword(s):  
Adipose Tissue ◽  
Fatty Acid ◽  
White Adipose Tissue ◽  
Fatty Acid Synthesis ◽  
Food Restriction ◽  
Glucose Utilization ◽  
Acid Synthesis ◽  
Anatomical Location ◽  
Standard Laboratory Diet

The effects of food restriction (limited access to food for 2 h/day for 10 days) on lipoprotein lipase (LPL) activities and rates of fatty acid synthesis and glucose utilization in vivo in two superficial (interscapular and subcutaneous) and three deep abdominal white adipose tissue depots (parametrial, perirenal, and mesenteric) of adult female Wistar rats were examined before and at 2 h after a standard laboratory diet meal (5 g). Fasting LPL activities in perirenal (1.6-fold), mesenteric (5.9-fold), and subcutaneous (2.7-fold) adipose tissue, when expressed per unit of delipidated tissue, were increased in response to food restriction. This effect was retained (but not enhanced) after the meal. In contrast, muscle LPL activities were either unchanged or suppressed by food restriction. Stimulation of adipose tissue fatty acid synthesis and glucose utilization evoked by feeding in control rats was greatly enhanced by prior food restriction. There was no relationship between anatomical location and presence or absence of the response of adipose tissue LPL activity to food restriction, but the effect of food restriction to enhance the responses of fatty acid synthesis and glucose utilization to a meal was more marked in perirenal and parametrial adipose tissue than in the more superficial depots. The results thus demonstrate regional specificity in the response of adipose tissue functions to food restriction.

scholarly journals A method to quantify glucose utilization in vivo in skeletal muscle and white adipose tissue of the anaesthetized rat

1985 ◽  
Vol 228 (1) ◽  
pp. 103-110 ◽  
Author(s):  
P Ferré ◽  
A Leturque ◽  
A F Burnol ◽  
L Penicaud ◽  
J Girard
Keyword(s):  
Adipose Tissue ◽  
White Adipose Tissue ◽  
Glucose Utilization ◽  
Correction Factors ◽  
Arterial Blood ◽  
Time Period ◽  
Anaesthetized Rat

A quantitative method allowing determination of glucose metabolism in vivo in muscles and white adipose tissue of the anaesthetized rat is presented. A tracer dose of 2-deoxy[3H]glucose was injected intravenously in an anaesthetized rat and the concentration of 2-deoxy[3H]glucose was monitored in arterial blood. After 30-80 min, three muscles, the soleus, the extensor digitorum longus and the epitrochlearis, periovarian white adipose tissue and brain were sampled and analysed for their content of 2-deoxy[3H]glucose 6-phosphate. This content could be related to glucose utilization during the same time period, since (1) the integral of the decrease of 2-deoxy[3H]glucose in arterial blood was known and (2) correction factors for the analogue effect of 2-deoxyglucose compared with glucose in the transport and phosphorylation steps were determined from experiments in vitro. Glucose utilization was then measured by this technique in the tissues of post-absorptive rats in the basal state (0.1 munit of insulin/ml of plasma) or during euglycaemic-hyperinsulinaemic glucose clamp (8 munits of insulin/ml of plasma) and of 48 h-starved rats. Results corresponded qualitatively and quantitatively to the known physiological characteristics of the tissues studied.

scholarly journals Metformin alleviates hyperuricaemia-induced serum FFA elevation and insulin resistance by inhibiting adipocyte hypertrophy and reversing suppressed white adipose tissue beiging

2020 ◽  
Vol 134 (12) ◽  
pp. 1537-1553
Author(s):  
Mengqi Su ◽  
Li Sun ◽  
Wenpeng Li ◽  
He Liu ◽  
Yang Liu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
White Adipose Tissue ◽  
High Serum ◽  
Whole Body ◽  
Sequencing Analysis ◽  
Underlying Mechanisms ◽  
High Level

Abstract Hyperuricaemia (HUA) significantly increases the risk of metabolic syndrome and is strongly associated with the increased prevalence of high serum free fatty acids (FFAs) and insulin resistance. However, the underlying mechanisms are not well established, especially the effect of uric acid (UA) on adipose tissue, a vital organ in regulating whole-body energy and FFA homeostasis. In the present study, we noticed that adipocytes from the white adipose tissue of patients with HUA were hypertrophied and had decreased UCP1 expression. To test the effects of UA on adipose tissue, we built both in vitro and in vivo HUA models and elucidated that a high level of UA could induce hypertrophy of adipocytes, inhibit their hyperplasia and reduce their beige-like characteristics. According to mRNA-sequencing analysis, UA significantly decreased the expression of leptin in adipocytes, which was closely related to fatty acid metabolism and the AMPK signalling pathway, as indicated by KEGG pathway analysis. Moreover, lowering UA using benzbromarone (a uricosuric agent) or metformin-induced activation of AMPK expression significantly attenuated UA-induced FFA metabolism impairment and adipose beiging suppression, which subsequently alleviated serum FFA elevation and insulin resistance in HUA mice. Taken together, these observations confirm that UA is involved in the aetiology of metabolic abnormalities in adipose tissue by regulating leptin-AMPK pathway, and metformin could lessen HUA-induced serum FFA elevation and insulin resistance by improving adipose tissue function via AMPK activation. Therefore, metformin could represent a novel treatment strategy for HUA-related metabolic disorders.

scholarly journals Effect of inhibition of glutathione synthesis on insulin action: in vivo and in vitro studies using buthionine sulfoximine

2000 ◽  
Vol 349 (2) ◽  
pp. 579-586 ◽  
Author(s):  
Mogher KHAMAISI ◽  
Oren KAVEL ◽  
Moti ROSENSTOCK ◽  
Michal PORAT ◽  
Michal YULI ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Insulin Secretion ◽  
Insulin Action ◽  
Impaired Insulin ◽  
Insulin Responsiveness

Decreased cellular GSH content is a common finding in experimental and human diabetes, in which increased oxidative stress appears to occur. Oxidative stress has been suggested to play a causative role in the development of impaired insulin action on adipose tissue and skeletal muscle. In this study we undertook to investigate the potential of GSH depletion to induce insulin resistance, by utilizing the GSH synthesis inhibitor, L-buthionine-[S,R]-sulfoximine (BSO). GSH depletion (20-80% in various tissues), was achieved in vivo by treating rats for 20 days with BSO, and in vitro (80%) by treating 3T3-L1 adipocytes with BSO for 18 h. No demonstrable change in the GSH/GSSG ratio was observed following BSO treatment. GSH depletion was progressively associated with abnormal glucose tolerance test, which could not be attributed to impaired insulin secretion. Skeletal muscle insulin responsiveness was unaffected by GSH depletion, based on normal glucose response to exogenous insulin, 2-deoxyglucose uptake measurements in isolated soleus muscle, and on normal skeletal muscle expression of GLUT4 protein. Adipocyte insulin responsiveness in vitro was assessed in 3T3-L1 adipocytes, which displayed decreased insulin-stimulated tyrosine phosphorylation of insulin-receptor-substrate proteins and of the insulin receptor, but exaggerated protein kinase B phosphorylation. However, insulin-stimulated glucose uptake was unaffected by GSH depletion. In accordance, normal adipose tissue insulin sensitivity was observed in BSO-treated rats in vivo, as demonstrated by normal inhibition of circulating non-esterified fatty acid levels by endogenous insulin secretion. In conclusion, GSH depletion by BSO results in impaired glucose tolerance, but preserved adipocyte and skeletal muscle insulin responsiveness. This suggests that alternative oxidation-borne factors mediate the induction of peripheral insulin resistance by oxidative stress.

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