Comparison of the metabolic effects of GIP receptor antagonism and PYY(3-36) receptor activation in high fat fed mice

The gut hormone gastric inhibitory polypeptide (GIP) plays a key role in glucose homeostasis and lipid metabolism. This study investigated the effects of administration of a stable and specific GIP receptor antagonist, (Pro3)GIP, in mice previously fed a high-fat diet for 160 days to induce obesity and related diabetes. Daily intraperitoneal injection of (Pro3)GIP over 50 days significantly decreased body weight compared with saline-treated controls, with a modest increase in locomotor activity but no change of high-fat diet intake. Plasma glucose, glycated hemoglobin, and pancreatic insulin were restored to levels of chow-fed mice, and circulating triglyceride and cholesterol were significantly decreased. (Pro3)GIP treatment also significantly decreased circulating glucagon and corticosterone, but concentrations of GLP-1, GIP, resistin, and adiponectin were unchanged. Adipose tissue mass, adipocyte hypertrophy, and deposition of triglyceride in liver and muscle were significantly decreased. These changes were accompanied by significant improvement of insulin sensitivity, meal tolerance, and normalization of glucose tolerance in (Pro3)GIP-treated high-fat-fed mice. (Pro3)GIP concentrations peaked rapidly and remained elevated 24 h after injection. These data indicate that GIP receptor antagonism using (Pro3)GIP provides an effective means of countering obesity and related diabetes induced by consumption of a high-fat, energy-rich diet.

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Impaired adipose expansion caused by liver X receptor activation is associated with insulin resistance in mice fed a high-fat diet

Journal of Molecular Endocrinology ◽

10.1530/jme-16-0196 ◽

2017 ◽

Vol 58 (3) ◽

pp. 141-154 ◽

Cited By ~ 5

Author(s):

Yueting Dong ◽

Zhiye Xu ◽

Ziyi Zhang ◽

Xueyao Yin ◽

Xihua Lin ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Glucose Uptake ◽

High Fat Diet ◽

Insulin Response ◽

Receptor Activation ◽

Metabolic Effects ◽

Whole Body ◽

High Fat ◽

Epididymal Fat

Liver X receptors (LXR) are deemed as potential drug targets for atherosclerosis, whereas a role in adipose tissue expansion and its relation to insulin sensitivity remains unclear. To assess the metabolic effects of LXR activation by the dual LXRα/β agonist T0901317, C57BL/6 mice fed a high-fat diet (HFD) were treated with T0901317 (30 mg/kg once daily by intraperitoneal injection) for 3 weeks. Differentiated 3T3-L1 adipocytes were used for analysing the effect of T0901317 on glucose uptake. The following results were obtained from this study. T0901317 reduced fat mass, accompanied by a massive fatty liver and lower serum adipokine levels in HFD mice. Increased adipocyte apoptosis was found in epididymal fat of T0901317-treated HFD mice. In addition, T0901317 treatment promoted basal lipolysis, but blunted the anti-lipolytic action of insulin. Furthermore, LXR activation antagonised PPARγ target genes in epididymal fat and PPARγ-PPRE-binding activity in 3T3-L1 adipocytes. Although the glucose tolerance was comparable to that in HFD mice, the insulin response during IPGTT was significantly higher and the insulin tolerance was significantly impaired in T0901317-treated HFD mice, indicating decreased insulin sensitivity by T0901317 administration, and which was further supported by impaired insulin signalling found in epididymal fat and decreased insulin-induced glucose uptake in 3T3-L1 adipocytes by T0901317 administration. In conclusion, these findings reveal that LXR activation impairs adipose expansion by increasing adipocyte apoptosis, lipolysis and antagonising PPARγ-mediated transcriptional activity, which contributes to decreased insulin sensitivity in whole body. The potential of LXR activation being a therapeutic target for atherosclerosis might be limited by the possibility of exacerbating insulin resistance.

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Metabolic Effects of the Sweet Protein MNEI as a Sweetener in Drinking Water. A Pilot Study of a High Fat Dietary Regimen in a Rodent Model

Nutrients ◽

10.3390/nu11112643 ◽

2019 ◽

Vol 11 (11) ◽

pp. 2643

Author(s):

Rosa Cancelliere ◽

Serena Leone ◽

Cristina Gatto ◽

Arianna Mazzoli ◽

Carmine Ercole ◽

...

Keyword(s):

Metabolic Syndrome ◽

Lipid Profile ◽

Western Diet ◽

Metabolic Effects ◽

High Fat ◽

Metabolic Derangement ◽

Dietary Regimen ◽

Sweet Proteins ◽

Sweet Protein ◽

Typical Western Diet

Sweeteners have become integrating components of the typical western diet, in response to the spreading of sugar-related pathologies (diabetes, obesity and metabolic syndrome) that have stemmed from the adoption of unbalanced dietary habits. Sweet proteins are a relatively unstudied class of sweet compounds that could serve as innovative sweeteners, but their introduction on the food market has been delayed by some factors, among which is the lack of thorough metabolic and toxicological studies. We have tried to shed light on the potential of a sweet protein, MNEI, as a fructose substitute in beverages in a typical western diet, by studying the metabolic consequences of its consumption on a Wistar rat model of high fat diet-induced obesity. In particular, we investigated the lipid profile, insulin sensitivity and other indicators of metabolic syndrome. We also evaluated systemic inflammation and potential colon damage. MNEI consumption rescued the metabolic derangement elicited by the intake of fructose, namely insulin resistance, altered plasma lipid profile, colon inflammation and translocation of lipopolysaccharides from the gut lumen into the circulatory system. We concluded that MNEI could represent a valid alternative to fructose, particularly when concomitant metabolic disorders such as diabetes and/or glucose intolerance are present.

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Metabolic effects of benzylidene thiazolidinedione derivatives in high-fat fed mice

Medicinal Chemistry Research ◽

10.1007/s00044-011-9764-4 ◽

2011 ◽

Vol 21 (9) ◽

pp. 2408-2414 ◽

Cited By ~ 4

Author(s):

Tiago Gomes Araújo ◽

Bruno Melo Carvalho ◽

Caíque Silveira Martins da Fonseca ◽

Maria do Carmo Alves de Lima ◽

Suely Lins Galdino ◽

...

Keyword(s):

Metabolic Effects ◽

High Fat

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Abstract 037: Role of Pro-opiomelanocortin (POMC) Specific PTP1B in Differential Regulation of Blood Pressure, Liver Lipid Accumulation and Glucose Tolerance in Response to a High Fat Diet

Hypertension ◽

10.1161/hyp.68.suppl_1.037 ◽

2016 ◽

Vol 68 (suppl_1) ◽

Author(s):

Nicola Aberdein ◽

Jussara M do Carmo ◽

Zhen Wang ◽

Taolin Fang ◽

Cecilia P de Lara ◽

...

Keyword(s):

Blood Pressure ◽

Glucose Tolerance ◽

Fat Mass ◽

Lipid Accumulation ◽

High Fat Diet ◽

Acute Stress ◽

Liver Lipid ◽

Liver Weight ◽

Metabolic Effects ◽

High Fat

Obese subjects are often resistant to leptin’s metabolic effects although blood pressure (BP) and sympathetic nervous system responses appear to be preserved. Protein tyrosine phosphatase 1B (PTP1B), a negative regulator of leptin signaling, may play a role in promoting this selective leptin resistance and causing metabolic dysfunction in obesity. Our previous studies suggest that the chronic BP responses to leptin are mediated via activation of pro-opiomelanocortin (POMC) neurons. The goal of this study was to determine if PTP1B in POMC neurons differentially controls metabolic functions and BP in mice fed a high fat diet (HFD). Male mice with POMC specific PTP1B deletion (POMC/PTP1B -/- ) and littermate controls (PTP1B flox/flox ) were fed a HFD from 6 to 22 wks of age. Baseline BP after 16 weeks of a HFD (95±2 vs. 95±3 mmHg) and BP responses to acute stress (Δ32±0 vs. Δ32±6 mmHg), measured by telemetry, were not different in POMC/PTP1B -/- compared to control mice, respectively. Heart rate (HR) was not different in POMC/PTP1B -/- and control mice during acute stress (699±4 vs. 697±15 bpm, respectively). Total body weight (TBW) and fat mass were reduced at 20 weeks of age in POMC/PTP1B -/- compared to controls (36.7±0.1 vs. 42.0±1 g TBW and 12.7±0.4 vs. 16.1±1.0 g fat mass, respectively). Liver weight of POMC/PTP1B -/- mice was less than in controls, and this was evident even when liver weight was normalized as % of TBW (4.5±0.2 vs. 5.0±0.2 %). POMC/PTP1B -/- males had reduced liver lipid accumulation compared to controls as measured by EchoMRI (0.08±0.03 vs. 0.15±0.03 g/g liver weight). Glucose tolerance was also improved by 46% in POMC/PTP1B -/- compared to controls as measured by AUC, 25856±1683 vs. 47267±5616 mg/dLx120min, respectively. These findings indicate that PTP1B signaling in POMC neurons plays a crucial role in regulating liver lipid accumulation and glucose tolerance but does not appear to mediate changes in BP or BP responses to acute stress in mice fed a high HFD (supported by NHLBI-PO1HL51971 and NIGMS P20GM104357)

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Regulation of motor neuron dendrite growth by NMDA receptor activation

Development ◽

10.1242/dev.120.11.3063 ◽

1994 ◽

Vol 120 (11) ◽

pp. 3063-3071 ◽

Cited By ~ 1

Author(s):

R.G. Kalb

Keyword(s):

Nmda Receptor ◽

Motor Neuron ◽

Cell Body ◽

Motor Neurons ◽

Receptor Activation ◽

Dendrite Growth ◽

Postnatal Life ◽

Receptor Antagonism ◽

Neuron Cell Body ◽

Early Postnatal Life

Spinal motor neurons undergo great changes in morphology, electrophysiology and molecular composition during development. Some of this maturation occurs postnatally when limbs are employed for locomotion, suggesting that neuronal activity may influence motor neuron development. To identify features of motor neurons that might be regulated by activity we first examined the structural development of the rat motor neuron cell body and dendritic tree labeled with cholera toxin-conjugated horseradish peroxidase. The motor neuron cell body and dendrites in the radial and rostrocaudal axes grew progressively over the first month of life. In contrast, the growth of the dendritic arbor/cell and number of dendritic branches was biphasic with overabundant growth followed by regression until the adult pattern was achieved. We next examined the influence of neurotransmission on the development of these motor neuron features. We found that antagonism of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor inhibited cell body growth and dendritic branching in early postnatal life but had no effect on the maximal extent of dendrite growth in the radial and rostrocaudal axes. The effects of NMDA receptor antagonism on motor neurons and their dendrites was temporally restricted; all of our anatomic measures of dendrite structure were resistant to NMDA receptor antagonism in adults. These results suggest that the establishment of mature motor neuron dendritic architecture results in part from dendrite growth in response to afferent input during a sensitive period in early postnatal life.

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