Ghrelin stimulation of growth hormone isoforms: parallel secretion of total and 20-kDa growth hormone and relation to insulin sensitivity in healthy humans.

CONTEXT: The 20-kDa human GH (hGH) is produced in the pituitary by alternative splicing of the hGH-N gene. The 20-kDa hGH promotes growth similarly to 22-kDa or total hGH, the predominant form in circulation, but the relative effects of these isoforms on glucose metabolism have been debated. OBJECTIVE: To investigate the effect of ghrelin on 20-kDa and total hGH secretion in healthy, nonobese subjects. We also studied associations between basal GH concentration and fasting glucose and insulin as well as between dynamic GH secretion and insulin sensitivity. DESIGN AND SETTING: Synthetic human acyl ghrelin (0.2 or 0.6 nmol/kg · h) or saline was infused in random order in 14 healthy subjects (six males, eight females; age 27.7 ± 6.3 yr; body mass index 22.0 ± 2.7 kg/m(2), mean ± SEM) on 3 separate days. Ghrelin was infused for 45 min to achieve steady-state levels and continued through a 3-h frequently sampled i.v. glucose tolerance test. Insulin sensitivity index was quantified using the minimal model of glucose kinetics. RESULTS: Basal 20-kDa and total GH concentrations were 0.4 ± 0.1 and 2.2 ± 0.4 ng/ml, respectively, with a 20-kDa to total GH ratio of 0.13 ± 0.02. Females had significantly higher baseline GH levels. Ghrelin administration increased 20-kDa and total GH levels in a parallel and dose-dependent fashion, with no significant change in the ratio of the isoforms. Basal 20-kDa and total GH levels were negatively correlated with fasting glucose, insulin, and homeostasis model assessment of insulin resistance. During the frequently sampled iv glucose tolerance test, GH secretion was positively correlated with insulin sensitivity index with saline infusion. CONCLUSION: Ghrelin dose-dependently increases endogenous 20-kDa and total GH secretion in a parallel fashion in healthy subjects. Both basal and stimulated levels of the different GH isoforms were positively associated with insulin sensitivity in this cohort of healthy men and women.

Carbohydrate content of post-operative diet influences the effect of vertical sleeve gastrectomy on body weight reduction in obese rats.

BACKGROUND: Vertical sleeve gastrectomy (VSG) effectively reduces body weight (BW) in obese rats and humans. However, post-surgical weight regain is frequently observed in subjects after VSG, but the underlying reasons remain poorly understood. We therefore investigated if post-surgical consumption of different diets can affect the outcome of VSG. METHODS: VSG or sham operation was performed in Long-Evans rats with diet-induced obesity (n = 37). After post-surgical recovery, rats were fed ad libitum either with standard chow (CH), high-fat (HF) or low-carbohydrate, high-fat (LCHF) diets. BW and food intake were measured every second day; serum leptin, cholesterol, HDL cholesterol, and triglycerides were analyzed 4 weeks after surgery. Energy expenditure and locomotor activity were determined by a combined indirect calorimetry system, lean and fat mass by nuclear magnetic resonance. RESULTS: After 4 weeks, BW gain, fat mass, and leptin were lower in VSG rats when compared to sham controls (p < 0.05). Energy expenditure and locomotor activity were not affected by VSG indicating that weight reduction derives from the significantly lower cumulative 4-week energy intake in VSG compared to sham. Sham rats fed LCHF consumed the most energy, followed by rats fed HF. In contrast, after VSG cumulative energy intake was highest in rats fed HF, but not different between CH and LCHF. Consistently, post-surgical BW and fat mass regain were highest in the HF-VSG group. Lipid profiles were improved by VSG but not differentially affected by diets. CONCLUSION: In conclusion, consumption of a HF diet but not the more energy-dense LCHF diet reduced the effectiveness of VSG in rats.

Isoenergetic feeding of low carbohydrate-high fat diets does not increase brown adipose tissue thermogenic capacity in rats.

UNLABELLED: Low-carbohydrate, high-fat (LC-HF) diets are popular for inducing weight loss in overweighed adults. Adaptive thermogenesis increased by specific effects of macronutrients on energy expenditure has been postulated to induce this weight loss. We studied brown adipose tissue (BAT) morphology and function following exposure to different LC-HF diets. METHODS: Male Wistar rats were fed a standard control diet ad libitum or pair-fed isoenergetic amounts of three experimental diets for 4 weeks. The diets had the following macronutrient composition (% metabolizable energy: carbohydrates, fat, protein): control (64.3/16.7/19), LC-HF-low protein (LC-HF-LP, 1.7/92.8/5.5), LC-HF-normal-protein (LC-HF-NP, 2.2/78.7/19.1), and a high fat diet with carbohydrates ("high fat", 19.4/61.9/18.7). RESULTS: Body weight gain was reduced in all pair-fed experimental groups as compared to rats fed the control diet, with more pronounced effect in rats on LC-HF diets than on the high fat diet with carbohydrates. High fat diets increased expression of PGC1α and ADRB3 in BAT indicating higher SNS outflow. However, UCP1 mRNA expression and expression of UCP1 assessed by immunohistochemistry was not different between diet groups. In accordance, analysis of mitochondrial function in-vitro by extracellular flux analyser (Seahorse Bioscience) and measurement of inducible thermogenesis in vivo (primary endpoint), explored by indirect calorimetry following norepinephrine injection, did not show significant differences between groups. Histology of BAT revealed increased lipid droplet size in rats fed the high-fat diet and both LC-HF diets. CONCLUSION: All experimental diets upregulated expression of genes which are indicative for increased BAT activity. However, the functional measurements in vivo revealed no increase of inducible BAT thermogenesis. This indicates that lower body weight gain with LC-HF diets and a high fat diet in a pair-feeding setting is not caused by increased adaptive thermogenesis in BAT.