Endothelial function and weight loss: Comparison of low‐carbohydrate and low‐fat diets

Objective: The effect of weight loss on obesity‐associated endothelial dysfunction is not clear because of conflicting data, demonstrating both improvement and no change in endothelial function after weight loss in obese subjects. A 2‐year prospective study (n = 121) was conducted to examine: (1) the effect of obesity and weight loss (either a low‐carbohydrate or and low‐fat diet) on flow mediated vasodilatation (FMD), a measure of endothelial function. Design and Methods: Participants reduced body weight by 7.1% ± 4.4%, 8.7% ± 6.8%, 7.1% ± 7.8%, and 4.1% ± 7.7% at 3, 6, 12, and 24 months, respectively with no significant differences between the low‐fat and low‐carbohydrate groups. Results: Endothelial function was inversely correlated with waist circumference, triglyceride level, and directly correlated with leptin in obese persons prior to weight loss. These weight losses did not confer any improvements in FMD. There were no differences between the low‐fat and low‐carbohydrate diets in FMD at any time point. At 6 months (r = 0.26, P = 0.04) and 1 year (r =0.28, P = 0.03), there were positive correlations between change in FMD and change in leptin but not at 2 years. Conclusion: There was no significant improvement in endothelial function after 7.1% ± 7.8% weight loss at 1 year and 4.1% ± 7.7% at 2 years, achieved by either a low carbohydrate or a low fat diet.     

pRb is an obesity suppressor in hypothalamus and high‐fat diet inhibits pRb in this location

pRb is frequently inactivated in tumours by mutations or phosphorylation. Here, we investigated whether pRb plays a role in obesity. The Arcuate nucleus (ARC) in hypothalamus contains antagonizing POMC and AGRP/NPY neurons for negative and positive energy balance, respectively. Various aspects of ARC neurons are affected in high‐fat diet (HFD)‐induced obesity mouse model. Using this model, we show that HFD, as well as pharmacological activation of AMPK, induces pRb phosphorylation and E2F target gene de‐repression in ARC neurons. Some affected neurons express POMC; and deleting Rb1 in POMC neurons induces E2F target gene de‐repression, cell‐cycle re‐entry, apoptosis, and a hyperphagia‐obesity‐diabetes syndrome. These defects can be corrected by combined deletion of E2f1. In contrast, deleting Rb1 in the antagonizing AGRP/NPY neurons shows no effects. Thus, pRb‐E2F1 is an obesity suppression mechanism in ARC POMC neurons and HFD‐AMPK inhibits this mechanism by phosphorylating pRb in this location.     

A low‐glycemic diet lifestyle intervention improves fat utilization during exercise in older obese humans

Objective: To determine the influence of dietary glycemic index on exercise training‐induced adaptations in substrate oxidation in obesity. Design and Methods: Twenty older, obese individuals undertook 3 months of fully supervised aerobic exercise and were randomized to low‐ (LoGIX) or high‐glycemic (HiGIX) diets. Changes in indirect calorimetry (VO₂; VCO₂) were assessed at rest, during a hyperinsulinemic‐euglycemic clamp, and during submaximal exercise (walking: 65% VO₂max, 200 kcal energy expenditure). Intramyocellular lipid (IMCL) was measured by ¹H‐magnetic resonance spectroscopy. Results: Weight loss (?8.6 ± 1.1%) and improvements (P < 0.05) in VO₂max, glycemic control, fasting lipemia, and metabolic flexibility were similar for both LoGIX and HiGIX groups. During submaximal exercise, energy expenditure was higher following the intervention (P < 0.01) in both groups. Respiratory exchange ratio during exercise was unchanged in the LoGIX group but increased in the HiGIX group (P < 0.05). However, fat oxidation during exercise expressed in relation to changes in body weight was increased in the LoGIX group (+10.6 ± 3.6%; P < 0.05). Fasting IMCL was unchanged, however, extramyocellular lipid was reduced (P < 0.05) after LoGIX. Conclusions: A LoGIX/exercise weight‐loss intervention increased fat utilization during exercise independent of changes in energy expenditure. This highlights the potential therapeutic value of low‐glycemic foods for reversing metabolic defects in obesity.     

Early‐life exposure to high‐fat diet influences brain health in aging mice

Epidemiological studies have suggested a link between exposure to environmental factors early in life and susceptibility to neurodegenerative diseases in adulthood. In the short term, maternal diet is important for the growth and development of the fetus; however, it may also have long‐term effects on the health status of the offspring. Here, we investigate the effect that maternal high‐fat diet during gestation has on brain health of the offspring later in life. B6129SF2/J dams were fed a high‐fat diet during the 3 weeks’ gestation, then switched to standard chow diet after delivery. Offspring were always fed regular diet for the entire study and assessed in learning, memory, and brain pathology when 18 months old. Compared with offspring from control mothers, the ones from mothers exposed to high‐fat diet had significant better performance in learning and memory tests, which associated with an amelioration of synaptic integrity. Additionally, they had a significant reduction in total tau, a decrease in its pathological conformational changes and lower levels of caspase‐3‐cleaved isoforms. Our findings demonstrate that in utero exposure to high‐fat diet plays a protective role for offspring brain health later in life. They support the novel hypothesis that targeted dietary intervention specifically restricted to the gestation period could be implemented as preventative strategy for the age‐dependent decline in brain health.     

Doubled lifespan and patient‐like pathologies in progeria mice fed high‐fat diet

Hutchinson‐Gilford Progeria Syndrome (HGPS) is a devastating premature aging disease. Mouse models have been instrumental for understanding HGPS mechanisms and for testing therapies, which to date have had only marginal benefits in mice and patients. Barriers to developing effective therapies include the unknown etiology of progeria mice early death, seemingly unrelated to the reported atherosclerosis contributing to HGPS patient mortality, and mice not recapitulating the severity of human disease. Here, we show that progeria mice die from starvation and cachexia. Switching progeria mice approaching death from regular diet to high‐fat diet (HFD) rescues early lethality and ameliorates morbidity. Critically, feeding the mice only HFD delays aging and nearly doubles lifespan, which is the greatest lifespan extension recorded in progeria mice. The extended lifespan allows for progeria mice to develop degenerative aging pathologies of a severity that emulates the human disease. We propose that starvation and cachexia greatly influence progeria phenotypes and that nutritional/nutraceutical strategies might help modulate disease progression. Importantly, progeria mice on HFD provide a more clinically relevant animal model to study mechanisms of HGPS pathology and to test therapies.     

Alogliptin improves survival and health of mice on a high‐fat diet

Alogliptin is a commonly prescribed drug treating patients with type 2 diabetes. Here, we show that long‐term intervention with alogliptin (0.03% w/w in diet) improves survival and health of mice on a high‐fat diet. Alogliptin intervention takes beneficial effects associated with longevity, including increased insulin sensitivity, attenuated functionality decline, decreased organ pathology, preserved mitochondrial function, and reduced oxidative stress. Autophagy activation is proposed as an underlying mechanism of these beneficial effects. We conclude that alogliptin intervention could be considered as a potential strategy for extending lifespan and healthspan in obesity and overweight.     

Arterial stiffness,lifestyle intervention and a low‐calorie diet in morbidly obese patients—A nonrandomized clinical trial

Objective:

Arterial stiffness is an independent predictor of cardiovascular morbidity and mortality. This study aimed to compare the 7‐week effect of a low‐calorie diet (LCD) and an intensive lifestyle intervention program (ILI) on arterial stiffness in morbidly obese individuals.

Design and Methods:

Nonrandomized clinical trial. The LCD provided 900 kcal/day, and participants in the LCD group were instructed to maintain their habitual physical activity level. The ILI included two 90‐min supervised training sessions 3 days a week at moderate to high intensity (4‐8 METs) and a caloric restriction of 1000 kcal/day.

Results:

A total of 179 individuals completed the study, 88 (56 women) in the ILI group and 91 (57 women) in the LCD group. High‐fidelity applanation tonometry (Millar^®, Sphygmocor^®) was used to measure carotid‐femoral pulse wave velocity (PWV). After adjustment for relevant confounders, the ILI group had a significantly greater reduction in PWV than the LCD group; ?0.4 (?0.6, ?0.1) m/s, P = 0.004. When compared to the LCD group, the ILI group showed a larger reduction in systolic and diastolic blood pressure ?5 (?9, ?1) and ?5 (?7, ?2) mmHg, P = 0.038 and P ≤ 0.001 respectively, whereas no difference was observed regarding pulse pressure, P = 0.661. No significant differences between groups were found regarding the loss of fat mass, P = 0.259, but the loss of muscle mass was larger in the LCD group, 0.8 (0.5, 1.1) kg, P ≤ 0.001.

Conclusion:

Despite the limitations of a nonrandomized design, our findings indicate that for morbidly obese individuals a moderate caloric restriction combined with aerobic physical exercise is associated with a greater decline in PWV than a LCD alone.