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Combined neural inactivation of suppressor of cytokine signaling-3 and protein-tyrosine phosphatase-1B reveals additive, synergistic, and factor-specific roles in the regulation of body energy balance.

Briancon N, McNay DE, Maratos-Flier E, Flier JS - Diabetes (2010)

Bottom Line: The aim of this study was to investigate possible genetic interactions between these two genes to determine whether combined reduction in these inhibitory activities results in synergistic, epistatic, or additive effects on energy balance control.Nonetheless, combined inactivation of SOCS-3 and PTP-1B in brain revealed additive effects on several parameters, including partial resistance to DIO and associated glucose intolerance.These results show that the biological roles of SOCS-3 and PTP-1B do not fully overlap and that targeting both factors might improve therapeutic effects of their inhibition in obesity and type 2 diabetes.

View Article: PubMed Central - PubMed

Affiliation: Division of Endocrinology, Diabetes, and Metabolism, Center for Life Sciences, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.

ABSTRACT

Objective: The adipokine hormone leptin triggers signals in the brain that ultimately lead to decreased feeding and increased energy expenditure. However, obesity is most often associated with elevated plasma leptin levels and leptin resistance. Suppressor of cytokine signaling (SOCS)-3 and protein-tyrosine phosphatase 1B (PTP-1B) are two endogenous inhibitors of tyrosine kinase signaling pathways and suppress both insulin and leptin signaling via different molecular mechanisms. Brain-specific inactivation of these genes individually in the mouse partially protects against diet-induced obesity (DIO) and insulin resistance. The aim of this study was to investigate possible genetic interactions between these two genes to determine whether combined reduction in these inhibitory activities results in synergistic, epistatic, or additive effects on energy balance control.

Research design and methods: We generated mice with combined inactivation of the genes coding for SOCS-3 and PTP-1B in brain cells, examined their sensitivity to hormone action, and analyzed the contribution of each gene to the resulting phenotype.

Results: Surprisingly, the Nestin-Cre mice used to mediate gene inactivation displayed a phenotype. Nonetheless, combined inactivation of SOCS-3 and PTP-1B in brain revealed additive effects on several parameters, including partial resistance to DIO and associated glucose intolerance. In addition, synergistic effects were observed for body length and weight, suggesting possible compensatory mechanisms for the absence of either inhibitor. Moreover, a SOCS-3-specific lean phenotype was revealed on the standard diet.

Conclusions: These results show that the biological roles of SOCS-3 and PTP-1B do not fully overlap and that targeting both factors might improve therapeutic effects of their inhibition in obesity and type 2 diabetes.

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Related in: MedlinePlus

Energy expenditure is slightly but not significantly increased by combined gene deletions. A: Circulating leptin levels of 5-month-old animals (n = 4–6). Logarithmic transformation of data were applied for statistical analysis attributed to variance heterogeneity. B: Daily standard diet consumption of singly housed 27- to 31-week-old mice (n = 5–12). C and F: Ambulatory activity (C), oxygen consumption (D), heat generated (E), and respiratory quotient (F) were recorded over 48 h and shown as average per hour during light and dark cycles (n = 4–6). Oxygen consumption and heat are normalized for body weight to account for the animal size differences. NS, not significant. ***P < 0.001 by t test. Boxed text, two-way ANOVA (see legend of Fig. 1 for details).
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Figure 3: Energy expenditure is slightly but not significantly increased by combined gene deletions. A: Circulating leptin levels of 5-month-old animals (n = 4–6). Logarithmic transformation of data were applied for statistical analysis attributed to variance heterogeneity. B: Daily standard diet consumption of singly housed 27- to 31-week-old mice (n = 5–12). C and F: Ambulatory activity (C), oxygen consumption (D), heat generated (E), and respiratory quotient (F) were recorded over 48 h and shown as average per hour during light and dark cycles (n = 4–6). Oxygen consumption and heat are normalized for body weight to account for the animal size differences. NS, not significant. ***P < 0.001 by t test. Boxed text, two-way ANOVA (see legend of Fig. 1 for details).

Mentions: In line with lower adiposity, leptin levels were reduced in double mutants, and this was mainly attributed to the absence of SOCS-3 (Fig. 3A). However, neither food intake nor ambulatory activity was different from Nestin-Cre mice (Fig. 3B and C). A trend toward higher energy expenditure (oxygen consumption and generated heat per kilogram body weight) was observed but did not reach significance (Fig. 3D and E). Respiratory quotient was unchanged among mutants (Fig. 3F).


Combined neural inactivation of suppressor of cytokine signaling-3 and protein-tyrosine phosphatase-1B reveals additive, synergistic, and factor-specific roles in the regulation of body energy balance.

Briancon N, McNay DE, Maratos-Flier E, Flier JS - Diabetes (2010)

Energy expenditure is slightly but not significantly increased by combined gene deletions. A: Circulating leptin levels of 5-month-old animals (n = 4–6). Logarithmic transformation of data were applied for statistical analysis attributed to variance heterogeneity. B: Daily standard diet consumption of singly housed 27- to 31-week-old mice (n = 5–12). C and F: Ambulatory activity (C), oxygen consumption (D), heat generated (E), and respiratory quotient (F) were recorded over 48 h and shown as average per hour during light and dark cycles (n = 4–6). Oxygen consumption and heat are normalized for body weight to account for the animal size differences. NS, not significant. ***P < 0.001 by t test. Boxed text, two-way ANOVA (see legend of Fig. 1 for details).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2992768&req=5

Figure 3: Energy expenditure is slightly but not significantly increased by combined gene deletions. A: Circulating leptin levels of 5-month-old animals (n = 4–6). Logarithmic transformation of data were applied for statistical analysis attributed to variance heterogeneity. B: Daily standard diet consumption of singly housed 27- to 31-week-old mice (n = 5–12). C and F: Ambulatory activity (C), oxygen consumption (D), heat generated (E), and respiratory quotient (F) were recorded over 48 h and shown as average per hour during light and dark cycles (n = 4–6). Oxygen consumption and heat are normalized for body weight to account for the animal size differences. NS, not significant. ***P < 0.001 by t test. Boxed text, two-way ANOVA (see legend of Fig. 1 for details).
Mentions: In line with lower adiposity, leptin levels were reduced in double mutants, and this was mainly attributed to the absence of SOCS-3 (Fig. 3A). However, neither food intake nor ambulatory activity was different from Nestin-Cre mice (Fig. 3B and C). A trend toward higher energy expenditure (oxygen consumption and generated heat per kilogram body weight) was observed but did not reach significance (Fig. 3D and E). Respiratory quotient was unchanged among mutants (Fig. 3F).

Bottom Line: The aim of this study was to investigate possible genetic interactions between these two genes to determine whether combined reduction in these inhibitory activities results in synergistic, epistatic, or additive effects on energy balance control.Nonetheless, combined inactivation of SOCS-3 and PTP-1B in brain revealed additive effects on several parameters, including partial resistance to DIO and associated glucose intolerance.These results show that the biological roles of SOCS-3 and PTP-1B do not fully overlap and that targeting both factors might improve therapeutic effects of their inhibition in obesity and type 2 diabetes.

View Article: PubMed Central - PubMed

Affiliation: Division of Endocrinology, Diabetes, and Metabolism, Center for Life Sciences, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.

ABSTRACT

Objective: The adipokine hormone leptin triggers signals in the brain that ultimately lead to decreased feeding and increased energy expenditure. However, obesity is most often associated with elevated plasma leptin levels and leptin resistance. Suppressor of cytokine signaling (SOCS)-3 and protein-tyrosine phosphatase 1B (PTP-1B) are two endogenous inhibitors of tyrosine kinase signaling pathways and suppress both insulin and leptin signaling via different molecular mechanisms. Brain-specific inactivation of these genes individually in the mouse partially protects against diet-induced obesity (DIO) and insulin resistance. The aim of this study was to investigate possible genetic interactions between these two genes to determine whether combined reduction in these inhibitory activities results in synergistic, epistatic, or additive effects on energy balance control.

Research design and methods: We generated mice with combined inactivation of the genes coding for SOCS-3 and PTP-1B in brain cells, examined their sensitivity to hormone action, and analyzed the contribution of each gene to the resulting phenotype.

Results: Surprisingly, the Nestin-Cre mice used to mediate gene inactivation displayed a phenotype. Nonetheless, combined inactivation of SOCS-3 and PTP-1B in brain revealed additive effects on several parameters, including partial resistance to DIO and associated glucose intolerance. In addition, synergistic effects were observed for body length and weight, suggesting possible compensatory mechanisms for the absence of either inhibitor. Moreover, a SOCS-3-specific lean phenotype was revealed on the standard diet.

Conclusions: These results show that the biological roles of SOCS-3 and PTP-1B do not fully overlap and that targeting both factors might improve therapeutic effects of their inhibition in obesity and type 2 diabetes.

Show MeSH
Related in: MedlinePlus