High-Fat Diet During Mouse Pregnancy and Lactation Targets GIP-Regulated Metabolic Pathways in Adult Male Offspring

Abstract

Maternal obesity is a worldwide problem associated with increased risk of metabolic diseases in the offspring. Genetic deletion of the gastric inhibitory polypeptide (GIP) receptor (GIPR) prevents high-fat diet (HFD)-induced obesity in mice due to specific changes in energy and fat cell metabolism. We investigated whether GIP-associated pathways may be targeted by fetal programming and mimicked the situation by exposing pregnant mice to control or HFD during pregnancy (intrauterine [IU]) and lactation (L). Male wild-type (WT) and Gipr 2/2 offspring received control chow until 25 weeks of age followed by 20 weeks of HFD. Gipr 2/2 offspring of mice exposed to HFD during IU/L became insulin resistant and obese and exhibited increased adipose tissue inflammation and decreased peripheral tissue substrate utilization after being reintroduced to HFD, similar to WT mice on regular chow during IU/L. They showed decreased hypothalamic insulin sensitivity compared with Gipr 2/2 mice on control diet during IU/L.DNA methylation analysis revealed increased methylation of CpG dinucleotides and differential transcription factor binding of promoter regions of genes involved in lipid oxidation in the muscle of Gipr 2/2 offspring on HFD during IU/L, which were inversely correlated with gene expression levels. Our data identify GIP-regulated metabolic pathways that are targeted by fetal programming.Gastric inhibitory polypeptide (GIP) is released from the duodenum after nutrient intake and regulates postprandial insulin secretion (1). GIP is known for its anabolic effects in adipocytes (2) and has been shown to stimulate the activity of lipoprotein lipase in adipose tissue in vitro (3) (4). Genetic ablation of the GIP receptor (GIPR) protects from high-fat diet (HFD)-induced obesity and insulin resistance in mice (5). GIPR knockout (Gipr) mice use fat as energy substrate rather than storing it in adipocytes. Moreover, central appetite-regulating pathways are downregulated in ovariectomized female Gipr 2/2 mice (6), and energy expenditure is increased in Gipr 2/2 mice exposed to a high-glycemic index diet (7) or an HFD (8).Since Gipr 2/2 mice are protected from obesity when exposed to a postweaning HFD, we hypothesized that this phenotype may be lost when these mice were exposed to the same HFD during pregnancy (intrauterine [IU]) and lactation (L). The IU milieu has a persisting influence on the development of adult diseases (9,10). Maternal caloric malnutrition as well as overnutrition during IU and L can induce metabolic disturbances later in life in offspring (11,12). Animal studies have shown that mice exposed to a maternal HFD during IU/L and weaned onto a standard chow developed adiposity, insulin resistance, and hepatosteatosis later in life (13,14). Not only the diet during IU/L but also the postweaning diet is important for the manifestation of metabolic diseases. Studies investigating the interaction of an HFD during IU/L and postweaning usually apply the HFD continuously from premating throughout the end of the study in ...

High Glycemic Index Metabolic Damage – a Pivotal Role of GIP and GLP-1

“…In 6month-old mice exposed to a high-fat diet, the hypothalamic phosphorylation of mTOR ser2448 is decreased significantly in GIPR À/À mice. Further downstream, phosphorylation of S6kinase thr389 is nonsignificantly reduced, while its target protein S6 ser235/236 again shows significantly reduced phosphorylation [54]. At the transcript level, hypothalamic phosphatidylinositol 3-kinase mRNA is decreased in GIPR À/À mice, again supporting hypothalamic actions of GIP.…”

“…However, the intrauterine and postnatal exposure of GIPR À/À mice to a high-fat diet abolishes this protection, leading to similar obesity and insulin resistance upon exposure to a high-fat diet after 6 month as in control mice. The intrauterine programming involves changes in hypothalamic phosphorylation and mRNA expression of the AKT-signaling pathway, as described above [54]. The most striking alterations are observed in enzymes involved in increased fat oxidation in skeletal muscle cells, which do not express GIPRs.…”

“…The most striking alterations are observed in enzymes involved in increased fat oxidation in skeletal muscle cells, which do not express GIPRs. An investigation of the epigenetic signature showed increased methylation of functional response elements in the promoter of carnitine palmitoyltransferase (CPT)1a, which reduced the interaction with regulatory transcription factors [54]. This suggests that central GIP-related pathways are involved in programming of peripheral gene expression related to a reduction of fat oxidation (Figure 4 and see Outstanding Questions).…”

Does skeletal muscle have an ‘epi’‐memory? The role of epigenetics in nutritional programming, metabolic disease, aging and exercise

“…However, pigs are encouraged to eat high‐fat diets once born, and therefore, it may be suggested that their mothers may offer some kind of protection for their foetuses, as high‐fat diets during pregnancy in other mammalian and human studies seem to have only negative consequences for metabolic disease risk (Khan et al ., ; Srinivasan et al ., ; Elahi et al ., ). An important recent study in mice has also shown that high‐fat diets during both gestation and lactation result in insulin resistance and obesity in the offspring, with increased inflammation originating in the adipose tissue (Kruse et al ., ). An observation confirmed a background of genetic deletion of gastric inhibitory polypeptide receptor (GIPR) that has previously been shown to prevent high‐fat diet‐induced obesity (Kruse et al ., ).…”

“…An important recent study in mice has also shown that high‐fat diets during both gestation and lactation result in insulin resistance and obesity in the offspring, with increased inflammation originating in the adipose tissue (Kruse et al ., ). An observation confirmed a background of genetic deletion of gastric inhibitory polypeptide receptor (GIPR) that has previously been shown to prevent high‐fat diet‐induced obesity (Kruse et al ., ). However, if prenatal high‐fat diets are followed by normal diets consumed after pregnancy, it seems that offspring may not develop obesity but type II diabetes via increased cytokine activation, inflammation and mitochondrial dysfunction (Latouche et al ., ).…”