Mouse strain-dependent variation in obesity and glucose homeostasis in response to high-fat feeding

Montgomery, Magdalene K; Hallahan, Nicole; Brown, Simon H. J.; Liu, Menghan; Mitchell, Todd W.; Cooney, Gregory J.; Turner, Nigel

doi:10.1007/s00125-013-2846-8

Cited by 334 publications

(327 citation statements)

References 48 publications

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“…Consistent with the Balb genetic background of these mice, HFD did not affect glucose tolerance or the insulin response of WT mice, as determined by GTTs and ITTs (Fig. 3i,j) [22]. However, Lbp-null mice exhibited marked glucose intolerance and reduced insulin sensitivity on both a standard diet and HFD.…”

Section: Resultssupporting

confidence: 73%

Lipopolysaccharide-binding protein is a negative regulator of adipose tissue browning in mice and humans

et al. 2016

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Aims/hypothesis Adipocyte lipopolysaccharide-binding protein (LBP) biosynthesis is associated with obesity-induced adipose tissue dysfunction. Our purpose was to study the role of LBP in regulating the browning of adipose tissue. Methods Adult mice were maintained at 4°C for 3 weeks or treated with the β 3 -adrenergic agonist, CL316,243, for 1 week to induce the browning of white fat. Precursor cells from brown and white adipose tissues were cultured under differentiation-inducing conditions to yield brown and beige/ brite adipocytes, respectively. In vitro, Lbp was knocked down in 3T3-L1 adipocytes, and cells were treated with recombinant LBP or co-cultured in transwells with control 3T3-L1 adipocytes. Wild-type and Lbp-null mice, fed a standard or high fat diet (HFD) for 15 weeks, were also used in investigations. In humans, subcutaneous and visceral adipose tissue samples were obtained from a cohort of morbidly obese participants.Results The induction of white fat browning by exposure of mice to cold or CL316,243 treatment was strongly associated with decreased Lbp mRNA expression in white adipose tissue. The acquisition of the beige/brite phenotype in cultured cells was associated with downregulation of Lbp. Moreover, silencing of Lbp induced the expression of brown fat-related genes in adipocytes, whereas LBP treatment reversed this effect. Lbp-null mice exhibited the spontaneous induction of subcutaneous adipose tissue browning, as evidenced by a remarkable increase in Ucp1 and Dio2 gene expression and the appearance of multivacuolar adipocyte clusters. The amount of brown adipose tissue, and brown adipose tissue activity were also increased in Lbp-null mice. These changes were associated with decreased weight gain in Lbp-null mice and protection against HFD-induced inflammatory responses, as shown by reduced IL-6 levels. However, rather than improving glucose homeostasis, these effects led to glucose intolerance and insulin resistance. Conclusions/interpretation LBP is identified as a negative regulator of the browning process, which is likely to contribute to the obesity-promoting action of LBP. The deleterious metabolic effects of LBP deletion are compatible with the concept that the appropriate regulation of inflammatory pathways is necessary for a healthy systemic metabolic profile, regardless of body weight regulation.

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Section: Resultssupporting

confidence: 73%

Lipopolysaccharide-binding protein is a negative regulator of adipose tissue browning in mice and humans

et al. 2016

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“…2c and 6c). A recent report documented the skeletal muscle and liver lipid accumulation in five different strains of mice fed a HFD (Montgomery et al 2013). In accordance with the present study, this previous study (Montgomery et al 2013) also identified strain-specific differences in organ lipid accumulation between BALB/c and C57BL/6 mice.…”

Section: Discussionsupporting

confidence: 92%

“…Overexpression of Hsp72 does not alter heart size, insulin-stimulated glucose clearance, or fatty acid oxidation rate in Hsp72 BALB/c mice As our previous work on Hsp72 overexpression in skeletal muscle was predominantly carried out in mice on a BALB/c background (Chung et al 2008;Henstridge et al 2014) and considering different mouse strains can have different total levels and rates of lipid accumulation (Kahle et al 2013;Montgomery et al 2013), we also conducted analyses on the hearts from these mice. Similar to the Hsp72 Tg mice on the C57BL/6J background, no difference in heart mass was observed (Supp Fig.…”

Section: Hsp72mentioning

confidence: 99%

Genetic manipulation of cardiac Hsp72 levels does not alter substrate metabolism but reveals insights into high-fat feeding-induced cardiac insulin resistance

Henstridge

Estévez

Allen

et al. 2015

Cell Stress and Chaperones

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Heat shock protein 72 (Hsp72) protects cells against a variety of stressors, and multiple studies have suggested that Hsp72 plays a cardioprotective role. As skeletal muscle Hsp72 overexpression can protect against high-fat diet (HFD)-induced insulin resistance, alterations in substrate metabolism may be a mechanism by which Hsp72 is cardioprotective. We investigated the impact of transgenically overexpressing (Hsp72 Tg) or deleting Hsp72 (Hsp72 KO) on various aspects of cardiac metabolism. Mice were fed a normal chow (NC) or HFD for 12 weeks from 8 weeks of age to examine the impact of diet-induced obesity on metabolic parameters in the heart. The HFD resulted in an increase in cardiac fatty acid oxidation and a decrease in cardiac glucose oxidation and insulin-stimulated cardiac glucose clearance; however, there was no difference in Hsp72 Tg or Hsp72 KO mice in these rates compared with their respective wild-type control mice. Although HFD-induced cardiac insulin resistance was not rescued in the Hsp72 Tg mice, it was preserved in the skeletal muscle, suggesting tissue-specific effects of Hsp72 overexpression on substrate metabolism. Comparison of two different strains of mice (BALB/c vs. C57BL/6J) also identified strain-specific differences in regard to HFD-induced cardiac lipid accumulation and insulin resistance. These strain differences suggest that cardiac lipid accumulation can be dissociated from cardiac insulin resistance. Our study finds that genetic manipulation of Hsp72 does not lead to alterations in metabolic processes in cardiac tissue under resting conditions, but identifies mouse strain-specific differences in cardiac lipid accumulation and insulin-stimulated glucose clearance.

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“…Although fatty liver develops in response to a wide diversity of physiological perturbations, these perturbations result in a similar metabolic phenotype that includes insulin resistance, hyperglucagonemia, hypertriglyceridemia, hyperglycemia and hyperketonemia. Of note, mouse models that lack hepatic lipid accumulation retain insulin sensitivity during obesity (Chen et al 2002, Franckhauser et al 2002, Haemmerle et al 2006, Montgomery et al 2013. Similarly, metabolically healthy obese humans are insulin sensitive with significantly less liver fat accumulation than obese, insulin resistance individuals (Stefan et al 2008, T & Gonzalez FJ 1998 …”

Section: Resultsmentioning

confidence: 99%

Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones

Geisler

Renquist

2017

Journal of Endocrinology

141

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Fatty liver can be diet, endocrine, drug, virus or genetically induced. Independent of cause, hepatic lipid accumulation promotes systemic metabolic dysfunction. By acting as peroxisome proliferator-activated receptor (PPAR) ligands, hepatic non-esterified fatty acids upregulate expression of gluconeogenic, beta-oxidative, lipogenic and ketogenic genes, promoting hyperglycemia, hyperlipidemia and ketosis. The typical hormonal environment in fatty liver disease consists of hyperinsulinemia, hyperglucagonemia, hypercortisolemia, growth hormone deficiency and elevated sympathetic tone. These endocrine and metabolic changes further encourage hepatic steatosis by regulating adipose tissue lipolysis, liver lipid uptake, de novo lipogenesis (DNL), beta-oxidation, ketogenesis and lipid export. Hepatic lipid accumulation may be induced by 4 separate mechanisms: (1) increased hepatic uptake of circulating fatty acids, (2) increased hepatic de novo fatty acid synthesis, (3) decreased hepatic beta-oxidation and (4) decreased hepatic lipid export. This review will discuss the hormonal regulation of each mechanism comparing multiple physiological models of hepatic lipid accumulation. Nonalcoholic fatty liver disease (NAFLD) is typified by increased hepatic lipid uptake, synthesis, oxidation and export. Chronic hepatic lipid signaling through PPARgamma results in gene expression changes that allow concurrent activity of DNL and beta-oxidation. The importance of hepatic steatosis in driving systemic metabolic dysfunction is highlighted by the common endocrine and metabolic disturbances across many conditions that result in fatty liver. Understanding the mechanisms underlying the metabolic dysfunction that develops as a consequence of hepatic lipid accumulation is critical to identifying points of intervention in this increasingly prevalent disease state.

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Mouse strain-dependent variation in obesity and glucose homeostasis in response to high-fat feeding

Cited by 334 publications

References 48 publications

Lipopolysaccharide-binding protein is a negative regulator of adipose tissue browning in mice and humans

Lipopolysaccharide-binding protein is a negative regulator of adipose tissue browning in mice and humans

Genetic manipulation of cardiac Hsp72 levels does not alter substrate metabolism but reveals insights into high-fat feeding-induced cardiac insulin resistance

Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones

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