Intestinal-derived FGF15 protects against deleterious effects of vertical sleeve gastrectomy in mice

Bariatric surgeries such as the Vertical Sleeve Gastrectomy (VSG) are invasive but provide the most effective improvements in obesity and Type 2 diabetes. We hypothesized a potential role for the gut hormone Fibroblast-Growth Factor 15/19 which is increased after VSG and pharmacologically can improve energy homeostasis and glucose handling. We generated intestinal-specific FGF15 knockout (FGF15INT-KO) mice which were maintained on high-fat diet. FGF15INT-KO mice lost more weight after VSG as a result of increased lean tissue loss. FGF15INT-KO mice also lost more bone density and bone marrow adipose tissue after VSG. The effect of VSG to improve glucose tolerance was also absent in FGF15INT-KO. VSG resulted in increased plasma bile acid levels but were considerably higher in VSG-FGF15INT-KO mice. These data point to an important role after VSG for intestinal FGF15 to protect the organism from deleterious effects of VSG potentially by limiting the increase in circulating bile acids.http://deepblue.lib.umich.edu/bitstream/2027.42/169579/2/s41467-021-24914-y.pdfAccepted versio

The GOAT-Ghrelin System Is Not Essential for Hypoglycemia Prevention during Prolonged Calorie Restriction

Ghrelin acylation by ghrelin O-acyltransferase (GOAT) has recently been reported to be essential for the prevention of hypoglycemia during prolonged negative energy balance. Using a unique set of four different genetic loss-of-function models for the GOAT/ghrelin/growth hormone secretagogue receptor (GHSR) system, we thoroughly tested the hypothesis that lack-of-ghrelin activation or signaling would lead to hypoglycemia during caloric deprivation. Male and female knockout (KO) mice for GOAT, ghrelin, GHSR, or both ghrelin and GHSR (dKO) were subjected to prolonged calorie restriction (40% of ad libitum chow intake). Body weight, fat mass, and glucose levels were recorded daily and compared to wildtype (WT) controls. Forty-eight hour blood glucose profiles were generated for each individual mouse when 2% or less body fat mass was reached. Blood samples were obtained for analysis of circulating levels of acyl- and desacyl-ghrelin, IGF-1, and insulin. Chronic calorie restriction progressively decreased body weight and body fat mass in all mice regardless of genotype. When fat mass was depleted to 2% or less of body weight for 2 consecutive days, random hypoglycemic events occurred in some mice across all genotypes. There was no increase in the incidence of hypoglycemia in any of the four loss-of-function models for ghrelin signaling including GOAT KO mice. Furthermore, no differences in insulin or IGF-1 levels were observed between genotypes. The endogenous GOAT-ghrelin-GHSR system is not essential for the maintenance of euglycemia during prolonged calorie restriction

GLP-1 based therapeutics: Simultaneously combating T2DM and obesity

Glucagon-like peptide-1 (GLP-1) enhances meal-related insulin secretion, which lowers blood glucose excursions. In addition to its incretin action, GLP-1 acts on the GLP-1 receptor (GLP-1R) in the brain to suppress feeding. These combined actions of GLP-1R signaling cause improvements in glycemic control as well as weight loss in type II diabetes (T2DM) patients treated with GLP-1R agonists. This is a superior advantage of GLP-1R pharmaceuticals as many other drugs used to treat T2DM are weight neutral or actual cause weight gain. This review summarizes GLP-1R action on energy and glucose metabolism, the effectiveness of current GLP-1R agonists on weight loss in T2DM patients, as well as GLP-1R combination therapies

GOAT ablation does not improve glucose homeostasis in mice on a leptin-deficient ob/ob background.

<p>a) Fasting insulin levels in 4-month-old chow-fed WT, GOAT-KO, ob/ob mutant and GOAT-ob/ob mice. b) Glucose tolerance tests (b left panel; 1 g glucose/kg body weight) in chow-fed mice revealed no improvement in glucose tolerance by GOAT ablation. Insulin tolerance tests in mice fed with MCT diet (b right panel; 0.75 U insulin/kg body weight) suggested severe insulin resistance in both GOAT-ob/ob and ob/ob mutant mice, and a normal insulin sensitivity in GOAT-KO and dWT mice. (n = 6–10).</p

Body weight, fat mass and fat free mass in male mice lacking GOAT on a leptin-deficient ob/ob background.

<p>GOAT-ob/ob mice fed standard chow diet display no differences in body weight (a), fat mass (b), or fat free mass (c), compared to ob/ob littermates. However, both leptin-deficient mutants differ significantly in their body adiposity from GOAT-KO and dWT mice, respectively. ** P<0.01 (1-way ANOVA); (n = 5–7).</p

Total ghrelin levels in WT and GOAT-KO mice on a normal or leptin-deficient ob/ob background.

<p>GOAT-KO and GOAT-ob/ob mice with a complete lack of acyl ghrelin have increased plasma concentration of total (desacyl) ghrelin. Total ghrelin levels are lower in both ob/ob as well as GOAT-ob/ob mice, compared to lean WT controls or GOAT-KO mice on chow diet. ^# P<0.05 versus dWT; ** P<0.001 versus GOAT-KO; ^$$ P<0.001 versus ob/ob; n = 4–7.</p

Genotyping conditions.

<p>Fwd, forward; Rev, reverse; bp, base pairs; Mboat4, Membrane bound-O-acyl transferase 4; ob, obese.</p

Metabolic phenotypes of ob/ob mutants and GOAT-ob/ob double mutants after exposure to medium-chain triglyceride (MCT) enriched diet.

<p>Leptin-deficient ob/ob and GOAT-ob/ob double mutant mice were fed MCT diet for 8 weeks. No differences were observed for body weight (a) and fat mass or fat free mass (b). Further, indirect calorimetry after 7 weeks of MCT diet exposure revealed no differences in food intake (c), energy expenditure (d), respiratory quotients (e) or locomotor activity (f, P = 0.16). (n = 4–7).</p

Acylation type determines ghrelin's effects on energy homeostasis in rodents

Ghrelin is a gastrointestinal polypeptide that acts through the ghrelin receptor (GHSR) to promote food intake and increase adiposity. Activation of GHSR requires the presence of a fatty-acid (FA) side chain on amino acid residue serine 3 of the ghrelin molecule. However, little is known about the role that the type of FA used for acylation plays in the biological action of ghrelin. We therefore evaluated a series of differentially acylated peptides to determine whether alterations in length or stability of the FA side chain have an impact on the ability of ghrelin to activate GHSR in vitro or to differentially alter food intake, body weight, and body composition in vivo. Fatty acids principally available in the diet (such as palmitate C16) and therefore representing potential substrates for the ghrelin-activating enzyme ghrelin O-acyltransferase (GOAT) were used for dose-, time-, and administration/route-dependent effects of ghrelin on food intake, body weight, and body composition in rats and mice. Our data demonstrate that altering the length of the FA side chain of ghrelin results in the differential activation of GHSR. Additionally, we found that acylation of ghrelin with a long-chain FA (C16) delays the acute central stimulation of food intake. Lastly, we found that, depending on acylation length, systemic and central chronic actions of ghrelin on adiposity can be enhanced or reduced. Together our data suggest that modification of the FA side-chain length can be a novel approach to modulate the efficacy of pharmacologically administered ghrelin