Contribution of the hypothalamus and gut to weight gain susceptibility and resistance in mice

Abstract

Obesity susceptibility in humans and in rodent strains varies in response to the consumption of high-energy density (HED) diets. However, the exact mechanism(s) involved in this susceptibility remain(s) unresolved. The aim of the present study was to gain greater insight into this susceptibility by using C57BL/6J (B6) mice that were separated into obesity-prone (diet-induced obese (DIO)) and obesity-resistant (diet-induced resistant (DR)) groups following an HED diet for 6 weeks. Physiological, biochemical and gene expression assessments of energy balance were performed in the DIO and DR mice on an HED diet and chow-fed mice. The increased weight gain of the DIO mice as compared to the DR mice was associated with increased energy intake and higher plasma leptin and adiponectin levels but not with reduced physical activity or resting energy expenditure. Hypothalamic Pomc gene expression was elevated, but there were no changes in Npy or Agrp expression. Adipose tissue leptin and adiponectin gene expression were significantly reduced in the DIO group as compared to the DR group. Interestingly, ileum expression of G protein-coupled receptor (Gpr) 40 (Gpr40) was significantly increased, whereas Gpr120, Gpr119, Gpr41, and glucagon-like peptide 1 (Glp1) were reduced. Contrastingly, the lower weight gain of the DR group was associated with elevated adipose tissue leptin and adiponectin gene expression, but there were no differences in plasma hormone or hypothalamic gene expression levels as compared to chow-fed mice. Therefore, the present data demonstrate that susceptibility and resistance to diet-induced weight gain in B6 mice appears to be predominantly driven by peripheral rather than hypothalamic modifications, and changes in gut-specific receptors are a potentially important contributor to this variation. Key Words" diet-induced obesity " high-energy density diet " body weight regulation

Complex Pharmacology of Free Fatty Acid Receptors

“…Most notably, FFA4 expression was upregulated in diet-induced obesity (DIO) rat models, 316,317 while it was downregulated in C57Bl6 mouse DIO models. 318 In studies measuring expression of FFA4 mRNA in human duodenum, a direct correlation was observed between body mass index and FFA4 transcript levels, 319 seeming to match well with the observations in DIO rats. Interestingly, FFA4 expression levels in cultured Caco-2 intestinal epithelial cells appear to be regulated by different species of gut microbiota, perhaps suggesting that FFA4 may have an indirect role in linking gut microbiota to health.…”

“…Interestingly, several factors seem to regulate FFA4 expression in the intestine, and these may be species and/or strain dependent. Most notably, FFA4 expression was upregulated in diet-induced obesity (DIO) rat models, , while it was downregulated in C57Bl6 mouse DIO models . In studies measuring expression of FFA4 mRNA in human duodenum, a direct correlation was observed between body mass index and FFA4 transcript levels, seeming to match well with the observations in DIO rats.…”

Paracrine crosstalk between intestinal L- and D-cells controls secretion of glucagon-like peptide-1 in mice

“…The expression of SSTr1-5 was investigated using custom-designed 384-well quantitative PCR plates from Lonza, Denmark. Data are shown as expression relative to a mean of three housekeeping genes, 18S ribosomal RNA, tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein (YWHAZ), and hypoxanthine phosphoribosyltransferase 1 (HPRT1) (15,55), and calculated using the Livak method (34). The sequences used for the five receptors and the housekeeping genes are listed in Supplemental Table S2 (https://doi.org/10.6084/m9.figshare.8307386) and published in Ref.…”

The androgen receptor in bone marrow progenitor cells negatively regulates fat mass

“…Food intake and voluntary physical activity were measured at 12 weeks of age and fasting energy expenditure was measured at 6 and 12 weeks of age as previously described (Cui et al 2015, Fam et al 2015. Briefly, food intake was determined in mice that were housed separately by weighing food each morning over a seven-day period and daily food intake averaged over the seven days.…”

“…Briefly, food intake was determined in mice that were housed separately by weighing food each morning over a seven-day period and daily food intake averaged over the seven days. Voluntary activity was measured by monitoring the use of running wheels with a computerised metre (Fam et al 2015) and fasting energy expenditure was determined by measuring the body weight of the mice prior to and following an overnight fast of 16 h and calculated as the change in body weight (Cui et al 2015).…”