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Deletion of Nhlh2 results in a defective torpor response and reduced Beta adrenergic receptor expression in adipose tissue.

Wankhade UD, Vella KR, Fox DL, Good DJ - PLoS ONE (2010)

Bottom Line: Gene and protein level expression of inflammatory and metabolic markers were compared between the two genotypes.This was accompanied by slight elevations of mRNA for several macrophage markers, including expression of macrophage specific protein F4/80 in adipose, suggestive of macrophage infiltration of WAT in the mutant animals.These studies implicate Nhlh2 in the central control of WAT and BAT function, with lack of Nhlh2 leading to adipose inflammation and altered gene expression, impaired leptin response to fasting, all suggestive of a deficient torpor response in mutant animals.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Nutrition, Foods and Exercise, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, United States of America.

ABSTRACT

Background: Mice with a targeted deletion of the basic helix-loop-helix transcription factor, Nescient Helix-Loop-Helix 2 (Nhlh2), display adult-onset obesity with significant increases in their fat depots, abnormal responses to cold exposure, and reduced spontaneous physical activity levels. These phenotypes, accompanied by the hypothalamic expression of Nhlh2, make the Nhlh2 knockout (N2KO) mouse a useful model to study the role of central nervous system (CNS) control on peripheral tissue such as adipose tissue.

Methodology: Differences in body temperature and serum analysis of leptin were performed in fasted and ad lib fed wild-type (WT) and N2KO mice. Histological analysis of white (WAT) and brown adipose tissue (BAT) was performed. Gene and protein level expression of inflammatory and metabolic markers were compared between the two genotypes.

Principal findings: We report significant differences in serum leptin levels and body temperature in N2KO mice compared with WT mice exposed to a 24-hour fast, suggestive of a defect in both white (WAT) and brown adipose tissue (BAT) function. As compared to WT mice, N2KO mice showed increased serum IL-6 protein and WAT IL-6 mRNA levels. This was accompanied by slight elevations of mRNA for several macrophage markers, including expression of macrophage specific protein F4/80 in adipose, suggestive of macrophage infiltration of WAT in the mutant animals. The mRNAs for beta3-adrenergic receptors (beta3-AR), beta2-AR and uncoupling proteins were significantly reduced in WAT and BAT from N2KO mice compared with WT mice.

Conclusions: These studies implicate Nhlh2 in the central control of WAT and BAT function, with lack of Nhlh2 leading to adipose inflammation and altered gene expression, impaired leptin response to fasting, all suggestive of a deficient torpor response in mutant animals.

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Serum leptin levels in ad lib fed and fasted WT and N2KO mice.Serum leptin was measured in WT and N2KO mice following ad libitum feeding (Ad lib), and following a 24 hour fast (Deprived). Data are reported as leptin concentration (pg/ml) ± SEM. (*p≤0.05).
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pone-0012324-g001: Serum leptin levels in ad lib fed and fasted WT and N2KO mice.Serum leptin was measured in WT and N2KO mice following ad libitum feeding (Ad lib), and following a 24 hour fast (Deprived). Data are reported as leptin concentration (pg/ml) ± SEM. (*p≤0.05).

Mentions: Ad libitum (ad lib) fed N2KO mice have normal food intake and leptin levels until they become overtly obese after 20 weeks of age [27]. Furthermore, food intake does not differ significantly in ad lib fed WT and N2KO mice measured over two hours, or in mice given two hours of feeding following a 24-hour fast [28]. As previously reported in pre-obese mice [29] and confirmed with these experiments, ad lib fed N2KO mice did not show significant differences in serum leptin levels when compared to ad lib fed WT mice. Interestingly, fasted N2KO mice presented a significant, 5.16-fold (*p≤0.05, T value = −2.99, df = 4) increase in serum leptin levels compared to WT mice. Consistent with expected results, fasted WT mice showed reduced serum leptin levels compared to ad lib fed WT mice (Fig 1).


Deletion of Nhlh2 results in a defective torpor response and reduced Beta adrenergic receptor expression in adipose tissue.

Wankhade UD, Vella KR, Fox DL, Good DJ - PLoS ONE (2010)

Serum leptin levels in ad lib fed and fasted WT and N2KO mice.Serum leptin was measured in WT and N2KO mice following ad libitum feeding (Ad lib), and following a 24 hour fast (Deprived). Data are reported as leptin concentration (pg/ml) ± SEM. (*p≤0.05).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2925948&req=5

pone-0012324-g001: Serum leptin levels in ad lib fed and fasted WT and N2KO mice.Serum leptin was measured in WT and N2KO mice following ad libitum feeding (Ad lib), and following a 24 hour fast (Deprived). Data are reported as leptin concentration (pg/ml) ± SEM. (*p≤0.05).
Mentions: Ad libitum (ad lib) fed N2KO mice have normal food intake and leptin levels until they become overtly obese after 20 weeks of age [27]. Furthermore, food intake does not differ significantly in ad lib fed WT and N2KO mice measured over two hours, or in mice given two hours of feeding following a 24-hour fast [28]. As previously reported in pre-obese mice [29] and confirmed with these experiments, ad lib fed N2KO mice did not show significant differences in serum leptin levels when compared to ad lib fed WT mice. Interestingly, fasted N2KO mice presented a significant, 5.16-fold (*p≤0.05, T value = −2.99, df = 4) increase in serum leptin levels compared to WT mice. Consistent with expected results, fasted WT mice showed reduced serum leptin levels compared to ad lib fed WT mice (Fig 1).

Bottom Line: Gene and protein level expression of inflammatory and metabolic markers were compared between the two genotypes.This was accompanied by slight elevations of mRNA for several macrophage markers, including expression of macrophage specific protein F4/80 in adipose, suggestive of macrophage infiltration of WAT in the mutant animals.These studies implicate Nhlh2 in the central control of WAT and BAT function, with lack of Nhlh2 leading to adipose inflammation and altered gene expression, impaired leptin response to fasting, all suggestive of a deficient torpor response in mutant animals.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Nutrition, Foods and Exercise, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, United States of America.

ABSTRACT

Background: Mice with a targeted deletion of the basic helix-loop-helix transcription factor, Nescient Helix-Loop-Helix 2 (Nhlh2), display adult-onset obesity with significant increases in their fat depots, abnormal responses to cold exposure, and reduced spontaneous physical activity levels. These phenotypes, accompanied by the hypothalamic expression of Nhlh2, make the Nhlh2 knockout (N2KO) mouse a useful model to study the role of central nervous system (CNS) control on peripheral tissue such as adipose tissue.

Methodology: Differences in body temperature and serum analysis of leptin were performed in fasted and ad lib fed wild-type (WT) and N2KO mice. Histological analysis of white (WAT) and brown adipose tissue (BAT) was performed. Gene and protein level expression of inflammatory and metabolic markers were compared between the two genotypes.

Principal findings: We report significant differences in serum leptin levels and body temperature in N2KO mice compared with WT mice exposed to a 24-hour fast, suggestive of a defect in both white (WAT) and brown adipose tissue (BAT) function. As compared to WT mice, N2KO mice showed increased serum IL-6 protein and WAT IL-6 mRNA levels. This was accompanied by slight elevations of mRNA for several macrophage markers, including expression of macrophage specific protein F4/80 in adipose, suggestive of macrophage infiltration of WAT in the mutant animals. The mRNAs for beta3-adrenergic receptors (beta3-AR), beta2-AR and uncoupling proteins were significantly reduced in WAT and BAT from N2KO mice compared with WT mice.

Conclusions: These studies implicate Nhlh2 in the central control of WAT and BAT function, with lack of Nhlh2 leading to adipose inflammation and altered gene expression, impaired leptin response to fasting, all suggestive of a deficient torpor response in mutant animals.

Show MeSH
Related in: MedlinePlus