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Structured Review

Jackson Laboratory insr floxed mice

(A) Structural view of insulin binding at site-1 of the insulin receptor (IR). Asp707 (red) within the αCT motif (blue) of the IR is a key residue mediating site-1 insulin interaction. (B) Representative images of WT, D707A/+, and D707A/D707A littermates at embryonic day 18.5 and at birth. (C) Genotype distribution of WT, D707A/+, and D707A/D707A mice at different ages. (D) Hematoxylin and Eosin (H&E) staining and periodic acid–Schiff (PAS) staining (magenta) of livers from WT and D707A/D707A newborn mice. (E) Breeding strategy used to generate conditional D707A/– mice. (F) Experimental scheme. Male and female mice (2–3 months old) were injected with tamoxifen for five consecutive days to delete the <t>floxed</t> WT IR allele and generate D707A/– mice. Data from male mice are shown in (G-L) and data from female mice are shown in . (G) Ad libitum blood glucose levels. D707A/F, n = 10; D707A/–, n = 12; –/–, n = 15. Data are presented as mean ± SEM; one-way ANOVA. (H) Fasting insulin levels. D707A/F, n = 9; D707A/–, n = 13; –/–, n = 7. Data are presented as mean ± SEM; one-way ANOVA. (I) Glucose tolerance test (GTT). Data are presented as mean ± SEM; two-way ANOVA; n = 8 mice per group; ****p < 0.0001. (J) Area under the curve (AUC) analysis of the GTT shown in (I). Data are presented as mean ± SEM; one-way ANOVA. (K) Percent change in body weight between pre-tamoxifen injection and the final day of the experiment. D707A/F, n = 8; D707A/–, n = 13; –/–, n =10. Data are presented as mean ± SEM; one-way ANOVA. (L) Representative H&E staining of pancreatic tissue.

Insr Floxed Mice, supplied by Jackson Laboratory, used in various techniques. Bioz Stars score: 86/100, based on 1 PubMed citations. ZERO BIAS - scores, article reviews, protocol conditions and more
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1) Product Images from "Reprogramming insulin receptor activation with a de novo agonist to overcome severe insulin resistance"

Article Title: Reprogramming insulin receptor activation with a de novo agonist to overcome severe insulin resistance

Journal: bioRxiv

doi: 10.64898/2026.05.04.722722

Figure Legend Snippet: (A) Structural view of insulin binding at site-1 of the insulin receptor (IR). Asp707 (red) within the αCT motif (blue) of the IR is a key residue mediating site-1 insulin interaction. (B) Representative images of WT, D707A/+, and D707A/D707A littermates at embryonic day 18.5 and at birth. (C) Genotype distribution of WT, D707A/+, and D707A/D707A mice at different ages. (D) Hematoxylin and Eosin (H&E) staining and periodic acid–Schiff (PAS) staining (magenta) of livers from WT and D707A/D707A newborn mice. (E) Breeding strategy used to generate conditional D707A/– mice. (F) Experimental scheme. Male and female mice (2–3 months old) were injected with tamoxifen for five consecutive days to delete the floxed WT IR allele and generate D707A/– mice. Data from male mice are shown in (G-L) and data from female mice are shown in . (G) Ad libitum blood glucose levels. D707A/F, n = 10; D707A/–, n = 12; –/–, n = 15. Data are presented as mean ± SEM; one-way ANOVA. (H) Fasting insulin levels. D707A/F, n = 9; D707A/–, n = 13; –/–, n = 7. Data are presented as mean ± SEM; one-way ANOVA. (I) Glucose tolerance test (GTT). Data are presented as mean ± SEM; two-way ANOVA; n = 8 mice per group; ****p < 0.0001. (J) Area under the curve (AUC) analysis of the GTT shown in (I). Data are presented as mean ± SEM; one-way ANOVA. (K) Percent change in body weight between pre-tamoxifen injection and the final day of the experiment. D707A/F, n = 8; D707A/–, n = 13; –/–, n =10. Data are presented as mean ± SEM; one-way ANOVA. (L) Representative H&E staining of pancreatic tissue.

Techniques Used: Binding Assay, Residue, Staining, Injection

(A) Experimental scheme. Female mice (2–3 months old) were injected with tamoxifen for five consecutive days to delete the floxed WT IR allele and generate D707A/– mice. Mice were fasted for 4 h and injected with PBS, 6 nmol/mouse Humulin or RF-409 via the inferior vena cava (IVC). Liver, skeletal muscle, and adipose tissue were collected at 3, 5, and 7 min after injection, respectively. (B) Representative immunoblot of IR autophosphorylation, AKT phosphorylation (pAKT), and ERK phosphorylation (pERK) in skeletal muscle from IR D707A/– mice. (C) Quantification of immunoblot data shown in (B). Data are presented as mean ± SEM; PBS, n = 4; Humulin, n = 5; RF-409, n = 5; one-way ANOVA. (D) Representative immunoblot of IR autophosphorylation, pAKT, and pERK in adipose tissue from IR D707A/– mice. (E) Quantification of immunoblot data shown in (D). Data are presented as mean ± SEM; PBS, n = 4; Humulin, n = 5; RF-409, n = 5; one-way ANOVA.

Figure Legend Snippet: (A) Experimental scheme. Female mice (2–3 months old) were injected with tamoxifen for five consecutive days to delete the floxed WT IR allele and generate D707A/– mice. Mice were fasted for 4 h and injected with PBS, 6 nmol/mouse Humulin or RF-409 via the inferior vena cava (IVC). Liver, skeletal muscle, and adipose tissue were collected at 3, 5, and 7 min after injection, respectively. (B) Representative immunoblot of IR autophosphorylation, AKT phosphorylation (pAKT), and ERK phosphorylation (pERK) in skeletal muscle from IR D707A/– mice. (C) Quantification of immunoblot data shown in (B). Data are presented as mean ± SEM; PBS, n = 4; Humulin, n = 5; RF-409, n = 5; one-way ANOVA. (D) Representative immunoblot of IR autophosphorylation, pAKT, and pERK in adipose tissue from IR D707A/– mice. (E) Quantification of immunoblot data shown in (D). Data are presented as mean ± SEM; PBS, n = 4; Humulin, n = 5; RF-409, n = 5; one-way ANOVA.

Techniques Used: Injection, Western Blot, Phospho-proteomics

(A) Representative immunoblot of IR protein levels in liver and skeletal muscle from IR D707A/– and IR –/– mice following a 4 h fast. (B) Quantification of immunoblot data shown in (A). Data are presented as mean ± SEM; IR D707A/-, n = 5; IR –/–, n = 7; one-way ANOVA. (C) Representative immunoblot of insulin receptor (IR) autophosphorylation, AKT phosphorylation (pAKT), and ERK phosphorylation (pERK) in liver from IR D707A/– mice. Mice were fasted for 4 h and injected with PBS, Humulin (6 nmol/mouse), or RF-409 via the inferior vena cava (IVC). Liver tissue was collected 3 min after injection. (D) Quantification of immunoblot data shown in (C). Data are presented as mean ± SEM; PBS, n = 4; Humulin, n = 5; RF-409, n = 5; one-way ANOVA. (E) Representative immunoblot of IR autophosphorylation in primary hepatocytes isolated from IR D707A/F;Cre-ERT mice. Cells were treated with 4-hydroxytamoxifen (4-OHT) to delete the floxed WT IR allele and generate IR D707A/– hepatocytes, followed by stimulation with insulin or RF-409 at the indicated concentrations for 10 min. (F) Quantification of immunoblot data shown in (E). Phosphorylation levels were normalized to total protein and expressed relative to the response to 100 nM insulin. Data are presented as mean ± SEM; n = 3 independent experiments; ****p < 0.0001.

Figure Legend Snippet: (A) Representative immunoblot of IR protein levels in liver and skeletal muscle from IR D707A/– and IR –/– mice following a 4 h fast. (B) Quantification of immunoblot data shown in (A). Data are presented as mean ± SEM; IR D707A/-, n = 5; IR –/–, n = 7; one-way ANOVA. (C) Representative immunoblot of insulin receptor (IR) autophosphorylation, AKT phosphorylation (pAKT), and ERK phosphorylation (pERK) in liver from IR D707A/– mice. Mice were fasted for 4 h and injected with PBS, Humulin (6 nmol/mouse), or RF-409 via the inferior vena cava (IVC). Liver tissue was collected 3 min after injection. (D) Quantification of immunoblot data shown in (C). Data are presented as mean ± SEM; PBS, n = 4; Humulin, n = 5; RF-409, n = 5; one-way ANOVA. (E) Representative immunoblot of IR autophosphorylation in primary hepatocytes isolated from IR D707A/F;Cre-ERT mice. Cells were treated with 4-hydroxytamoxifen (4-OHT) to delete the floxed WT IR allele and generate IR D707A/– hepatocytes, followed by stimulation with insulin or RF-409 at the indicated concentrations for 10 min. (F) Quantification of immunoblot data shown in (E). Phosphorylation levels were normalized to total protein and expressed relative to the response to 100 nM insulin. Data are presented as mean ± SEM; n = 3 independent experiments; ****p < 0.0001.

Techniques Used: Western Blot, Phospho-proteomics, Injection, Isolation

(A) Experimental scheme for chronic RF-409 treatment. Male mice (3 months old) were injected with tamoxifen for five consecutive days to delete the floxed WT IR allele and generate IR D707A/– mice. Following the final tamoxifen injection, osmotic pumps releasing PBS or RF-409 were implanted. Body composition was assessed by MRI prior to tamoxifen injection and 14 days after the final tamoxifen injection. (B) Ad libitum blood glucose levels during the treatment period. Data are presented as mean ± SEM; n = 5 mice per treatment; two-way ANOVA; **p < 0.01. (C) Average ad libitum blood glucose levels calculated from (B). Data are presented as mean ± SEM; n = 5 mice per treatment; Welch’s t test. (D) Fasting insulin levels at the end of the treatment period. Data are presented as mean ± SEM; n = 5 mice per treatment; Welch’s t test. (E) Percent change in body weight over the treatment period. Data are presented as mean ± SEM; n = 5 mice per treatment; Welch’s t test. (F) Percent change in fat mass. Data are presented as mean ± SEM; n = 5 mice per treatment; Welch’s t test. (G) Percent change in lean mass. Data are presented as mean ± SEM; n = 5 mice per treatment; Welch’s t test. (H) Epididymal white adipose tissue (eWAT) weight normalized to body weight. Data are presented as mean ± SEM; n = 5 mice per treatment; Welch’s t test. (I) Representative H&E staining (top) and insulin immunostaining (bottom) of pancreatic tissue. (J) Pancreas weight normalized to body weight. Data are presented as mean ± SEM; n = 5 mice per treatment; Welch’s t test. (K) Acinar area quantification. Data are presented as mean ± SEM; n = 5 mice per treatment; Welch’s t test. (L) Representative H&E staining of liver tissue.

Figure Legend Snippet: (A) Experimental scheme for chronic RF-409 treatment. Male mice (3 months old) were injected with tamoxifen for five consecutive days to delete the floxed WT IR allele and generate IR D707A/– mice. Following the final tamoxifen injection, osmotic pumps releasing PBS or RF-409 were implanted. Body composition was assessed by MRI prior to tamoxifen injection and 14 days after the final tamoxifen injection. (B) Ad libitum blood glucose levels during the treatment period. Data are presented as mean ± SEM; n = 5 mice per treatment; two-way ANOVA; **p < 0.01. (C) Average ad libitum blood glucose levels calculated from (B). Data are presented as mean ± SEM; n = 5 mice per treatment; Welch’s t test. (D) Fasting insulin levels at the end of the treatment period. Data are presented as mean ± SEM; n = 5 mice per treatment; Welch’s t test. (E) Percent change in body weight over the treatment period. Data are presented as mean ± SEM; n = 5 mice per treatment; Welch’s t test. (F) Percent change in fat mass. Data are presented as mean ± SEM; n = 5 mice per treatment; Welch’s t test. (G) Percent change in lean mass. Data are presented as mean ± SEM; n = 5 mice per treatment; Welch’s t test. (H) Epididymal white adipose tissue (eWAT) weight normalized to body weight. Data are presented as mean ± SEM; n = 5 mice per treatment; Welch’s t test. (I) Representative H&E staining (top) and insulin immunostaining (bottom) of pancreatic tissue. (J) Pancreas weight normalized to body weight. Data are presented as mean ± SEM; n = 5 mice per treatment; Welch’s t test. (K) Acinar area quantification. Data are presented as mean ± SEM; n = 5 mice per treatment; Welch’s t test. (L) Representative H&E staining of liver tissue.

Techniques Used: Injection, Staining, Immunostaining

Mouse Assay:

Article Title: Reprogramming insulin receptor activation with a de novo agonist to overcome severe insulin resistance
Article Snippet: IR D707A/+ mice were backcrossed to a C57BL/6J background (The Jackson Laboratory, #000664) for at least three generations. .. Insr floxed mice (IR F/F ; The Jackson Laboratory, #006955) were crossed with tamoxifen-inducible CAG-CreERT mice( ) (The Jackson Laboratory, #004682) to generate IR F/F ;CreERT mice, which were subsequently backcrossed for nine generations onto the C57BL/6J background. ..

other:

Article Title: Insulin signaling in LepR cells modulates fat and glucose homeostasis independent of leptin
Article Snippet: The LepR-Cre [B6.129(Cg) – Lepr tme(cre)rck /J, stock no. 008320; JAX mice], the ob / ob (Lep ob ) (B6.Cg – Lep ob /J, stock no. 000632; JAX mice), and the InsR floxed [B6.12954(FVB) – Ins tm1khn /J, stock no. 006955; JAX mice] mice were housed in an Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC)-accredited facility at the University of Michigan.

Article Title: Insulin signaling in LepR cells modulates fat and glucose homeostasis independent of leptin.
Article Snippet: The LepR-Cre [B6.129(Cg) – Leprtme(cre)rck/J, stock no. 008320; JAX mice], the ob/ob (Lepob) (B6.Cg – Lepob/J, stock no. 000632; JAX mice), and the InsR floxed [B6.12954(FVB) – Instm1khn/J, stock no. 006955; JAX mice] mice were housed in an Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC)-accredited facility at the University of Michigan.

Image Search Results

Journal: bioRxiv

Article Title: Reprogramming insulin receptor activation with a de novo agonist to overcome severe insulin resistance

doi: 10.64898/2026.05.04.722722

Figure Lengend Snippet: (A) Structural view of insulin binding at site-1 of the insulin receptor (IR). Asp707 (red) within the αCT motif (blue) of the IR is a key residue mediating site-1 insulin interaction. (B) Representative images of WT, D707A/+, and D707A/D707A littermates at embryonic day 18.5 and at birth. (C) Genotype distribution of WT, D707A/+, and D707A/D707A mice at different ages. (D) Hematoxylin and Eosin (H&E) staining and periodic acid–Schiff (PAS) staining (magenta) of livers from WT and D707A/D707A newborn mice. (E) Breeding strategy used to generate conditional D707A/– mice. (F) Experimental scheme. Male and female mice (2–3 months old) were injected with tamoxifen for five consecutive days to delete the floxed WT IR allele and generate D707A/– mice. Data from male mice are shown in (G-L) and data from female mice are shown in . (G) Ad libitum blood glucose levels. D707A/F, n = 10; D707A/–, n = 12; –/–, n = 15. Data are presented as mean ± SEM; one-way ANOVA. (H) Fasting insulin levels. D707A/F, n = 9; D707A/–, n = 13; –/–, n = 7. Data are presented as mean ± SEM; one-way ANOVA. (I) Glucose tolerance test (GTT). Data are presented as mean ± SEM; two-way ANOVA; n = 8 mice per group; ****p < 0.0001. (J) Area under the curve (AUC) analysis of the GTT shown in (I). Data are presented as mean ± SEM; one-way ANOVA. (K) Percent change in body weight between pre-tamoxifen injection and the final day of the experiment. D707A/F, n = 8; D707A/–, n = 13; –/–, n =10. Data are presented as mean ± SEM; one-way ANOVA. (L) Representative H&E staining of pancreatic tissue.

Article Snippet: Insr floxed mice (IR F/F ; The Jackson Laboratory, #006955) were crossed with tamoxifen-inducible CAG-CreERT mice( ) (The Jackson Laboratory, #004682) to generate IR F/F ;CreERT mice, which were subsequently backcrossed for nine generations onto the C57BL/6J background.

Techniques: Binding Assay, Residue, Staining, Injection

Journal: bioRxiv

Article Title: Reprogramming insulin receptor activation with a de novo agonist to overcome severe insulin resistance

doi: 10.64898/2026.05.04.722722

Figure Lengend Snippet: (A) Experimental scheme. Female mice (2–3 months old) were injected with tamoxifen for five consecutive days to delete the floxed WT IR allele and generate D707A/– mice. Mice were fasted for 4 h and injected with PBS, 6 nmol/mouse Humulin or RF-409 via the inferior vena cava (IVC). Liver, skeletal muscle, and adipose tissue were collected at 3, 5, and 7 min after injection, respectively. (B) Representative immunoblot of IR autophosphorylation, AKT phosphorylation (pAKT), and ERK phosphorylation (pERK) in skeletal muscle from IR D707A/– mice. (C) Quantification of immunoblot data shown in (B). Data are presented as mean ± SEM; PBS, n = 4; Humulin, n = 5; RF-409, n = 5; one-way ANOVA. (D) Representative immunoblot of IR autophosphorylation, pAKT, and pERK in adipose tissue from IR D707A/– mice. (E) Quantification of immunoblot data shown in (D). Data are presented as mean ± SEM; PBS, n = 4; Humulin, n = 5; RF-409, n = 5; one-way ANOVA.

Techniques: Injection, Western Blot, Phospho-proteomics

Journal: bioRxiv

Article Title: Reprogramming insulin receptor activation with a de novo agonist to overcome severe insulin resistance

doi: 10.64898/2026.05.04.722722

Figure Lengend Snippet: (A) Representative immunoblot of IR protein levels in liver and skeletal muscle from IR D707A/– and IR –/– mice following a 4 h fast. (B) Quantification of immunoblot data shown in (A). Data are presented as mean ± SEM; IR D707A/-, n = 5; IR –/–, n = 7; one-way ANOVA. (C) Representative immunoblot of insulin receptor (IR) autophosphorylation, AKT phosphorylation (pAKT), and ERK phosphorylation (pERK) in liver from IR D707A/– mice. Mice were fasted for 4 h and injected with PBS, Humulin (6 nmol/mouse), or RF-409 via the inferior vena cava (IVC). Liver tissue was collected 3 min after injection. (D) Quantification of immunoblot data shown in (C). Data are presented as mean ± SEM; PBS, n = 4; Humulin, n = 5; RF-409, n = 5; one-way ANOVA. (E) Representative immunoblot of IR autophosphorylation in primary hepatocytes isolated from IR D707A/F;Cre-ERT mice. Cells were treated with 4-hydroxytamoxifen (4-OHT) to delete the floxed WT IR allele and generate IR D707A/– hepatocytes, followed by stimulation with insulin or RF-409 at the indicated concentrations for 10 min. (F) Quantification of immunoblot data shown in (E). Phosphorylation levels were normalized to total protein and expressed relative to the response to 100 nM insulin. Data are presented as mean ± SEM; n = 3 independent experiments; ****p < 0.0001.

Techniques: Western Blot, Phospho-proteomics, Injection, Isolation

Journal: bioRxiv

Article Title: Reprogramming insulin receptor activation with a de novo agonist to overcome severe insulin resistance

doi: 10.64898/2026.05.04.722722

Figure Lengend Snippet: (A) Experimental scheme for chronic RF-409 treatment. Male mice (3 months old) were injected with tamoxifen for five consecutive days to delete the floxed WT IR allele and generate IR D707A/– mice. Following the final tamoxifen injection, osmotic pumps releasing PBS or RF-409 were implanted. Body composition was assessed by MRI prior to tamoxifen injection and 14 days after the final tamoxifen injection. (B) Ad libitum blood glucose levels during the treatment period. Data are presented as mean ± SEM; n = 5 mice per treatment; two-way ANOVA; **p < 0.01. (C) Average ad libitum blood glucose levels calculated from (B). Data are presented as mean ± SEM; n = 5 mice per treatment; Welch’s t test. (D) Fasting insulin levels at the end of the treatment period. Data are presented as mean ± SEM; n = 5 mice per treatment; Welch’s t test. (E) Percent change in body weight over the treatment period. Data are presented as mean ± SEM; n = 5 mice per treatment; Welch’s t test. (F) Percent change in fat mass. Data are presented as mean ± SEM; n = 5 mice per treatment; Welch’s t test. (G) Percent change in lean mass. Data are presented as mean ± SEM; n = 5 mice per treatment; Welch’s t test. (H) Epididymal white adipose tissue (eWAT) weight normalized to body weight. Data are presented as mean ± SEM; n = 5 mice per treatment; Welch’s t test. (I) Representative H&E staining (top) and insulin immunostaining (bottom) of pancreatic tissue. (J) Pancreas weight normalized to body weight. Data are presented as mean ± SEM; n = 5 mice per treatment; Welch’s t test. (K) Acinar area quantification. Data are presented as mean ± SEM; n = 5 mice per treatment; Welch’s t test. (L) Representative H&E staining of liver tissue.

Techniques: Injection, Staining, Immunostaining

( A ) Insr (IR, encoding gene) mRNA levels in Ctrl and GLUT1 ΔGFAP mice after ACSA-2 + FACS-mediated isolation of astrocytes ( n = 6 mice per group). ( B ) ATP levels in microdialysis-isolated interstitial fluid of Ctrl and IR ∆GFAP mice before (basal) and after intraperitoneal glucose injection (0 to 30 and 30 to 60 min). Data are expressed as the percentage of their own basal ( n = 6 to 8 mice per group). ( C ) Schematic illustration of the strategy used to generate mice lacking IR specifically in astrocytes (IR ΔGFAP ) and their Ctrl littermates (IR f/f ), intracerebroventricular cannulation, and 2-MeSATP intracerebroventricular administration. Created with BioRender.com . ( D ) Glucose-induced suppression of feeding evaluated by 4-hour accumulated food intake in Ctrl and IR ΔGFAP mice subjected to HFD after saline or 2-MeSATP intracerebroventricular injection ( n = 6 to 11 per group). ( E ) GTT in saline-treated or 2-MeSATP intracerebroventricularly treated Ctrl and IR ΔGFAP mice on HFD ( n = 8 to 12 per group). ( F ) Spatial memory evaluation by MWM acquisition and ( G ) retention phase of saline-treated or 2-MeSATP intracerebroventricularly treated Ctrl and IR ΔGFAP mice on HFD ( n = 5 to 12 per group). Data are presented as means ± SEM. * P ≤ 0.05 as determined by two-tailed Student’s t test (A), repeated-measurement ANOVA (B, E, and F), and two-way ANOVA followed by Tukey (D and G).

Journal: Science Advances

Article Title: Astrocytic GLUT1 reduction paradoxically improves central and peripheral glucose homeostasis

doi: 10.1126/sciadv.adp1115

Figure Lengend Snippet: ( A ) Insr (IR, encoding gene) mRNA levels in Ctrl and GLUT1 ΔGFAP mice after ACSA-2 + FACS-mediated isolation of astrocytes ( n = 6 mice per group). ( B ) ATP levels in microdialysis-isolated interstitial fluid of Ctrl and IR ∆GFAP mice before (basal) and after intraperitoneal glucose injection (0 to 30 and 30 to 60 min). Data are expressed as the percentage of their own basal ( n = 6 to 8 mice per group). ( C ) Schematic illustration of the strategy used to generate mice lacking IR specifically in astrocytes (IR ΔGFAP ) and their Ctrl littermates (IR f/f ), intracerebroventricular cannulation, and 2-MeSATP intracerebroventricular administration. Created with BioRender.com . ( D ) Glucose-induced suppression of feeding evaluated by 4-hour accumulated food intake in Ctrl and IR ΔGFAP mice subjected to HFD after saline or 2-MeSATP intracerebroventricular injection ( n = 6 to 11 per group). ( E ) GTT in saline-treated or 2-MeSATP intracerebroventricularly treated Ctrl and IR ΔGFAP mice on HFD ( n = 8 to 12 per group). ( F ) Spatial memory evaluation by MWM acquisition and ( G ) retention phase of saline-treated or 2-MeSATP intracerebroventricularly treated Ctrl and IR ΔGFAP mice on HFD ( n = 5 to 12 per group). Data are presented as means ± SEM. * P ≤ 0.05 as determined by two-tailed Student’s t test (A), repeated-measurement ANOVA (B, E, and F), and two-way ANOVA followed by Tukey (D and G).

Article Snippet: Insr flox/flox (named IR f/f ) mice ( ) were purchased from The Jackson Laboratory [B6.129S4(FVB)-Insr tm1Khn /J; strain# 006955; RRID:IMSR_JAX:006955].

Techniques: Isolation, Injection, Saline, Two Tailed Test

Insulin directly inhibits parasympathetic preganglionic neurons. (A) Image demonstrating the location of the brainstem section (left) and a parasympathetic preganglionic neuron of the dorsal motor nucleus of the vagus nerve (DMV; right) targeted for whole-cell patch clamp recordings, obtained from ChAT cre/+ ::tdTomato mice. (B) Bright-field, tetramethylrhodamine (TRITC), fluorescein isothiocyanate (FITC), and merged images (from left to right) of the targeted neuron (arrows) in the DMV of ChAT cre/+ ::tdTomato mice. Scale bar=50 μm. (C) Membrane potential hyperpolarizes in response to insulin (50 nM) treatment. The dashed line indicates the baseline membrane potential. (D) Voltage responses to hyperpolarizing current steps from –50 to 0 pA, applied as indicated by arrows in (C). (E) The voltage-current relationship demonstrates insulin-induced decreases in input resistance. (F) Drawings of four rostrocaudal levels of the mouse brainstem summarize the location of the acute effects of insulin on parasympathetic preganglionic neurons. Blue dots indicate hyperpolarized cells, while black dots indicate cells with no effects. (G) The membrane potential hyperpolarized in response to insulin treatment in the presence of tetrodotoxin (TTX, 500 nM) and synaptic blockers (SBs, 1 mM kynurenic acid+50 μM picrotoxin). The dashed line indicates baseline membrane potential. (H) The membrane potential did not change after insulin treatment parasympathetic preganglionic neurons from ChAT cre/+ ::InsR f/f ::tdTomato mice. The dashed line indicates baseline membrane potential. (I) Plots summarizing insulin-induced changes in membrane potential. (J) Histogram summarizing the percentage of neurons showing insulin responses. ACSF, artificial cerebrospinal fluid; 4V, fourth ventricle; 12N, nucleus of the hypoglossal nerve; NTS, nucleus tractus solitaries; AP, area postrema; CC, central canal; Cu, nucleus cuneatus; Gr, nucleus gracilis; ChAT, choline acetyltransferase; InsR f/f , insulin receptor flox. a P <0.01, Fisher’s exact test for the occurrence of hyperpolarization and no effects.

Journal: Endocrinology and Metabolism

Article Title: Insulin Preferentially Regulates the Activity of Parasympathetic Preganglionic Neurons over Sympathetic Preganglionic Neurons

doi: 10.3803/EnM.2023.1725

Figure Lengend Snippet: Insulin directly inhibits parasympathetic preganglionic neurons. (A) Image demonstrating the location of the brainstem section (left) and a parasympathetic preganglionic neuron of the dorsal motor nucleus of the vagus nerve (DMV; right) targeted for whole-cell patch clamp recordings, obtained from ChAT cre/+ ::tdTomato mice. (B) Bright-field, tetramethylrhodamine (TRITC), fluorescein isothiocyanate (FITC), and merged images (from left to right) of the targeted neuron (arrows) in the DMV of ChAT cre/+ ::tdTomato mice. Scale bar=50 μm. (C) Membrane potential hyperpolarizes in response to insulin (50 nM) treatment. The dashed line indicates the baseline membrane potential. (D) Voltage responses to hyperpolarizing current steps from –50 to 0 pA, applied as indicated by arrows in (C). (E) The voltage-current relationship demonstrates insulin-induced decreases in input resistance. (F) Drawings of four rostrocaudal levels of the mouse brainstem summarize the location of the acute effects of insulin on parasympathetic preganglionic neurons. Blue dots indicate hyperpolarized cells, while black dots indicate cells with no effects. (G) The membrane potential hyperpolarized in response to insulin treatment in the presence of tetrodotoxin (TTX, 500 nM) and synaptic blockers (SBs, 1 mM kynurenic acid+50 μM picrotoxin). The dashed line indicates baseline membrane potential. (H) The membrane potential did not change after insulin treatment parasympathetic preganglionic neurons from ChAT cre/+ ::InsR f/f ::tdTomato mice. The dashed line indicates baseline membrane potential. (I) Plots summarizing insulin-induced changes in membrane potential. (J) Histogram summarizing the percentage of neurons showing insulin responses. ACSF, artificial cerebrospinal fluid; 4V, fourth ventricle; 12N, nucleus of the hypoglossal nerve; NTS, nucleus tractus solitaries; AP, area postrema; CC, central canal; Cu, nucleus cuneatus; Gr, nucleus gracilis; ChAT, choline acetyltransferase; InsR f/f , insulin receptor flox. a P <0.01, Fisher’s exact test for the occurrence of hyperpolarization and no effects.

Article Snippet: Insulin receptor flox (InsR f/f ) mice (#006955, Jackson Laboratory) were used for some experiments.

Techniques: Patch Clamp, Membrane

Insulin hyperpolarizes GABAergic neurons of the nucleus tractus solitaries (NTS) and dorsal motor nucleus of the vagus nerve (DMV). (A) Bright-field, tetramethylrhodamine (TRITC), fluorescein isothiocyanate (FITC), and merged images (from left to right) of the targeted neuron (arrows) in the NTS of Phox2bcre/+::tdTomato mice. Scale bar=50 μm. (B) The membrane potential hyperpolarized in response to insulin (50 nM) treatment. The dashed line indicates the baseline membrane potential. (C) Plots summarizing insulin-induced changes in membrane potential. (D) Bright-field, TRITC, FITC, and merged images (from left to right) of the targeted neuron (arrows) in the NTS of Vgat cre/+ ::tdTomato mice. Scale bar=50 μm. (E) The membrane potential hyperpolarized in response to insulin treatment. The dashed line indicates the baseline membrane potential. (F) Plots summarize insulin-induced changes in the membrane potential. (G) Bright-field, TRITC, FITC, and merged images (from left to right) of the targeted neuron (arrows) in the DMV of Vgat cre/+ ::tdTomato mice. Scale bar=50 μm. (H) The membrane potential hyperpolarized in response to insulin treatment. The dashed line indicates the baseline membrane potential. (I) Plots summarizing insulin-induced changes in the membrane potential. (J) Illustration summarizing modulation of parasympathetic preganglionic neurons and their upstream neurons by insulin and insulin receptors. Phox2b, paired-like homeobox 2b; Vgat, vesicular GABA transporter; ACSF, artificial cerebrospinal fluid; AP, area postrema; ChAT, choline acetyltransferase; InsR, insulin receptor; GABA, γ-aminobutyric acid.

Journal: Endocrinology and Metabolism

Article Title: Insulin Preferentially Regulates the Activity of Parasympathetic Preganglionic Neurons over Sympathetic Preganglionic Neurons

doi: 10.3803/EnM.2023.1725

Figure Lengend Snippet: Insulin hyperpolarizes GABAergic neurons of the nucleus tractus solitaries (NTS) and dorsal motor nucleus of the vagus nerve (DMV). (A) Bright-field, tetramethylrhodamine (TRITC), fluorescein isothiocyanate (FITC), and merged images (from left to right) of the targeted neuron (arrows) in the NTS of Phox2bcre/+::tdTomato mice. Scale bar=50 μm. (B) The membrane potential hyperpolarized in response to insulin (50 nM) treatment. The dashed line indicates the baseline membrane potential. (C) Plots summarizing insulin-induced changes in membrane potential. (D) Bright-field, TRITC, FITC, and merged images (from left to right) of the targeted neuron (arrows) in the NTS of Vgat cre/+ ::tdTomato mice. Scale bar=50 μm. (E) The membrane potential hyperpolarized in response to insulin treatment. The dashed line indicates the baseline membrane potential. (F) Plots summarize insulin-induced changes in the membrane potential. (G) Bright-field, TRITC, FITC, and merged images (from left to right) of the targeted neuron (arrows) in the DMV of Vgat cre/+ ::tdTomato mice. Scale bar=50 μm. (H) The membrane potential hyperpolarized in response to insulin treatment. The dashed line indicates the baseline membrane potential. (I) Plots summarizing insulin-induced changes in the membrane potential. (J) Illustration summarizing modulation of parasympathetic preganglionic neurons and their upstream neurons by insulin and insulin receptors. Phox2b, paired-like homeobox 2b; Vgat, vesicular GABA transporter; ACSF, artificial cerebrospinal fluid; AP, area postrema; ChAT, choline acetyltransferase; InsR, insulin receptor; GABA, γ-aminobutyric acid.

Article Snippet: Insulin receptor flox (InsR f/f ) mice (#006955, Jackson Laboratory) were used for some experiments.

Techniques: Membrane

Newborn offspring with placenta-specific InsR ablation presented with normal body weight and pancreatic β-cell mass. ( A ) Experimental schematic for generating InsR KO placenta and littermate controls. ( B ) GFP reporter (Cyp19-cre; CAG +/+ ) expressing endogenous green fluorescence (GFP) in a mouse embryonic E17.5 placenta section compared to the non-GFP control (CAG +/+ ) (scale bars: 500 μm). ( C ) InsR mRNA expression in the E17.5 InsR KO placenta compared to controls by quantitative reverse transcription polymerase chain reaction (qPCR) ( n = 12, 13). ( D ) Histology of the E17.5 male control placentas (left) compared to InsR KO placenta (right) (scale bars: 500 μm). Background of images was subtracted post-imaging. ( E ) Gross morphology of the male and ( E’ ) female control (left) and the InsR KO placenta (right) newborn pancreata. ( F ) Whole pancreatic sections (scale bars: 500 μm) of the male newborn control (left) and the InsR KO placenta (right) mice immunostained for insulin-positive islets (green) and DAPI (blue). Single islet β-cells (scale bars: 50 μm) shown as insets. Single islet images were cropped post-imaging to highlight the single islet. ( G ) Beta cell mass for the male ( n = 5) and ( G’ ) female ( n = 5) newborns. The values are reported as the means ± SEM, ** p <0.01. E: embryonic; P: postnatal; BW: body weight; BG: blood glucose; IPGTT: intraperitoneal glucose tolerance test; IPITT; intraperitoneal insulin tolerance test; NCD: normal chow diet.

Journal: Biomedicines

Article Title: Placental Insulin Receptor Transiently Regulates Glucose Homeostasis in the Adult Mouse Offspring of Multiparous Dams

doi: 10.3390/biomedicines10030575

Figure Lengend Snippet: Newborn offspring with placenta-specific InsR ablation presented with normal body weight and pancreatic β-cell mass. ( A ) Experimental schematic for generating InsR KO placenta and littermate controls. ( B ) GFP reporter (Cyp19-cre; CAG +/+ ) expressing endogenous green fluorescence (GFP) in a mouse embryonic E17.5 placenta section compared to the non-GFP control (CAG +/+ ) (scale bars: 500 μm). ( C ) InsR mRNA expression in the E17.5 InsR KO placenta compared to controls by quantitative reverse transcription polymerase chain reaction (qPCR) ( n = 12, 13). ( D ) Histology of the E17.5 male control placentas (left) compared to InsR KO placenta (right) (scale bars: 500 μm). Background of images was subtracted post-imaging. ( E ) Gross morphology of the male and ( E’ ) female control (left) and the InsR KO placenta (right) newborn pancreata. ( F ) Whole pancreatic sections (scale bars: 500 μm) of the male newborn control (left) and the InsR KO placenta (right) mice immunostained for insulin-positive islets (green) and DAPI (blue). Single islet β-cells (scale bars: 50 μm) shown as insets. Single islet images were cropped post-imaging to highlight the single islet. ( G ) Beta cell mass for the male ( n = 5) and ( G’ ) female ( n = 5) newborns. The values are reported as the means ± SEM, ** p <0.01. E: embryonic; P: postnatal; BW: body weight; BG: blood glucose; IPGTT: intraperitoneal glucose tolerance test; IPITT; intraperitoneal insulin tolerance test; NCD: normal chow diet.

Article Snippet: To generate placental trophoblast-specific insulin receptor knockout mice (Cyp19-cre; InsR f/f ) and their littermate controls (InsR f/f ), floxed InsR male mice (InsR f/f ) (purchased from Jackson Laboratory, stock No. 006955) were bred with floxed InsR female mice expressing the placenta-specific Cre recombinase (Cyp19-cre; InsR f/f ).

Techniques: Expressing, Fluorescence, Control, Reverse Transcription, Polymerase Chain Reaction, Imaging

Male and female offspring characteristics in newborns (P0) and adults (parity ≥ 3) on a normal chow diet. Newborn characteristics in terms of body weight, non-fasting blood glucose, non-fasting serum insulin, pancreas weight, and liver weight. Adult offspring characteristics in terms of fasting and non-fasting blood glucose levels measured at 9 and 10 weeks of age, respectively. The data are presented as the means ± SEM.

Journal: Biomedicines

Article Title: Placental Insulin Receptor Transiently Regulates Glucose Homeostasis in the Adult Mouse Offspring of Multiparous Dams

doi: 10.3390/biomedicines10030575

Figure Lengend Snippet: Male and female offspring characteristics in newborns (P0) and adults (parity ≥ 3) on a normal chow diet. Newborn characteristics in terms of body weight, non-fasting blood glucose, non-fasting serum insulin, pancreas weight, and liver weight. Adult offspring characteristics in terms of fasting and non-fasting blood glucose levels measured at 9 and 10 weeks of age, respectively. The data are presented as the means ± SEM.

Techniques: Control

Adult InsR KO placenta mice displayed normal glucose homeostasis on a normal chow diet. ( A ) Body weight in all the males ( n = 9, 10) and ( A’ ) the female ( n = 13) InsR KO placenta and control mice on a normal chow diet. Body weight for the offspring presented as combined data from parity ≥ 3 and ≤2 litters. ( B ) IPGTT and AUC analysis (right) for the male ( n = 4) and ( B’ ) female ( n = 4) mice from parity ≥ 3 on a normal chow diet at 9 weeks of age. ( C ) IPITT and AUC analysis (right) for the males ( n = 4) and ( C’ ) females ( n = 4) from parity ≥ 3 at 11 weeks of age. Blood glucose values for IPITT are expressed as the baseline percentage of blood glucose. The values are reported as the means ± SEM, * p < 0.05.

Journal: Biomedicines

Article Title: Placental Insulin Receptor Transiently Regulates Glucose Homeostasis in the Adult Mouse Offspring of Multiparous Dams

doi: 10.3390/biomedicines10030575

Figure Lengend Snippet: Adult InsR KO placenta mice displayed normal glucose homeostasis on a normal chow diet. ( A ) Body weight in all the males ( n = 9, 10) and ( A’ ) the female ( n = 13) InsR KO placenta and control mice on a normal chow diet. Body weight for the offspring presented as combined data from parity ≥ 3 and ≤2 litters. ( B ) IPGTT and AUC analysis (right) for the male ( n = 4) and ( B’ ) female ( n = 4) mice from parity ≥ 3 on a normal chow diet at 9 weeks of age. ( C ) IPITT and AUC analysis (right) for the males ( n = 4) and ( C’ ) females ( n = 4) from parity ≥ 3 at 11 weeks of age. Blood glucose values for IPITT are expressed as the baseline percentage of blood glucose. The values are reported as the means ± SEM, * p < 0.05.

Techniques: Control

Adult male InsR KO placenta offspring demonstrated lower body weight under a high-fat diet challenge. ( A ) Schematic of experimental design for a high-fat diet (HFD). ( B ) Body weight monitored in all the males ( n = 6, 7) and ( B’ ) females ( n = 8, 9) from parity ≥ 3 and ≤2 across 17 weeks on a HFD. ( C ) Non-fasting blood glucose levels for all the males ( n = 6, 7) and ( C’ ) females ( n = 8, 9) from parity was ≥3 and ≤2 (measured across 17 weeks on a HFD). Measurements not included for T = 4, 8, 10, 14, and 18 weeks on a HFD due to phenotyping performed on these weeks. ( D ) Fasting blood glucose measured for the males ( n = 4, 7) and ( D’ ) females ( n = 4, 9) from parity ≥ 3 and ≤2 at 4, 8, and 10 weeks on a HFD. ( E ) Fat mass for the males ( n = 6, 7) and ( E’ ) females ( n = 8, 9) from parity ≥ 3 and ≤2 as assessed by EchoMRI at 18–19 weeks on a HFD. ( F ) Lean mass for the males ( n = 6, 7) and ( F’ ) females ( n = 8, 9) from parity ≥ 3 and ≤2 as assessed by EchoMRI at 18–19 weeks on a HFD. ( G ) Pancreas weight for the males ( n = 6, 7) and ( G’ ) females ( n = 8, 9) from parity ≥ 3 and ≤2 upon harvest at 19–20 weeks on a HFD. The values are reported as the means ± SEM, * p < 0.05. P: postnatal; BW: body weight; BG: blood glucose; IPGTT: intraperitoneal glucose tolerance test; IPITT; intraperitoneal insulin tolerance test; HFD: high-fat diet.

Journal: Biomedicines

Article Title: Placental Insulin Receptor Transiently Regulates Glucose Homeostasis in the Adult Mouse Offspring of Multiparous Dams

doi: 10.3390/biomedicines10030575

Figure Lengend Snippet: Adult male InsR KO placenta offspring demonstrated lower body weight under a high-fat diet challenge. ( A ) Schematic of experimental design for a high-fat diet (HFD). ( B ) Body weight monitored in all the males ( n = 6, 7) and ( B’ ) females ( n = 8, 9) from parity ≥ 3 and ≤2 across 17 weeks on a HFD. ( C ) Non-fasting blood glucose levels for all the males ( n = 6, 7) and ( C’ ) females ( n = 8, 9) from parity was ≥3 and ≤2 (measured across 17 weeks on a HFD). Measurements not included for T = 4, 8, 10, 14, and 18 weeks on a HFD due to phenotyping performed on these weeks. ( D ) Fasting blood glucose measured for the males ( n = 4, 7) and ( D’ ) females ( n = 4, 9) from parity ≥ 3 and ≤2 at 4, 8, and 10 weeks on a HFD. ( E ) Fat mass for the males ( n = 6, 7) and ( E’ ) females ( n = 8, 9) from parity ≥ 3 and ≤2 as assessed by EchoMRI at 18–19 weeks on a HFD. ( F ) Lean mass for the males ( n = 6, 7) and ( F’ ) females ( n = 8, 9) from parity ≥ 3 and ≤2 as assessed by EchoMRI at 18–19 weeks on a HFD. ( G ) Pancreas weight for the males ( n = 6, 7) and ( G’ ) females ( n = 8, 9) from parity ≥ 3 and ≤2 upon harvest at 19–20 weeks on a HFD. The values are reported as the means ± SEM, * p < 0.05. P: postnatal; BW: body weight; BG: blood glucose; IPGTT: intraperitoneal glucose tolerance test; IPITT; intraperitoneal insulin tolerance test; HFD: high-fat diet.

Techniques:

Adult male InsR KO placenta mice from multiparous dams presented with a mild and transient improved glucose homeostasis on a high-fat diet challenge. ( A ) IPGTT and AUC analysis (right) for the male ( n = 4) and ( A’ ) female ( n = 4) mice from parity ≥ 3 at 8 weeks on a HFD. Repeated measures two-way ANOVA revealed significant differences ( p = 0.0332) between the InsR KO placenta and control males at 8 weeks on a HFD. A separate unpaired t -test performed specifically for T = 60 min revealed p = 0.0593. ( B ) IPITT and AUC analysis (right) for the males ( n = 4) and ( B’ ) females ( n = 4) from parity ≥ 3 at 14 weeks on a HFD. Blood glucose values for IPITT are expressed as the baseline percentage of blood glucose. Repeated measures two-way ANOVA analysis revealed a p -value of 0.0867 in the males at 14 weeks on a HFD. A separate unpaired t -test performed specifically for T = 30 and T = 60 min revealed p = 0.0843 and p = 0.0600, respectively. The values are reported as the means ± SEM, * p < 0.05.

Journal: Biomedicines

Article Title: Placental Insulin Receptor Transiently Regulates Glucose Homeostasis in the Adult Mouse Offspring of Multiparous Dams

doi: 10.3390/biomedicines10030575

Figure Lengend Snippet: Adult male InsR KO placenta mice from multiparous dams presented with a mild and transient improved glucose homeostasis on a high-fat diet challenge. ( A ) IPGTT and AUC analysis (right) for the male ( n = 4) and ( A’ ) female ( n = 4) mice from parity ≥ 3 at 8 weeks on a HFD. Repeated measures two-way ANOVA revealed significant differences ( p = 0.0332) between the InsR KO placenta and control males at 8 weeks on a HFD. A separate unpaired t -test performed specifically for T = 60 min revealed p = 0.0593. ( B ) IPITT and AUC analysis (right) for the males ( n = 4) and ( B’ ) females ( n = 4) from parity ≥ 3 at 14 weeks on a HFD. Blood glucose values for IPITT are expressed as the baseline percentage of blood glucose. Repeated measures two-way ANOVA analysis revealed a p -value of 0.0867 in the males at 14 weeks on a HFD. A separate unpaired t -test performed specifically for T = 30 and T = 60 min revealed p = 0.0843 and p = 0.0600, respectively. The values are reported as the means ± SEM, * p < 0.05.

Techniques: Control

Journal: Biomedicines

Article Title: Placental Insulin Receptor Transiently Regulates Glucose Homeostasis in the Adult Mouse Offspring of Multiparous Dams

doi: 10.3390/biomedicines10030575

Techniques: Expressing, Fluorescence, Control, Reverse Transcription, Polymerase Chain Reaction, Imaging

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insr floxed mice (Jackson Laboratory)

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