Responses of the Adult Rat Glucose Metabolism to Early Life Feeding, Caloric Restriction and Refeeding

Early life overfeeding in the rat can be experimentally induced by reducing litter size. This investigation assessed the consequences of this manipulation on glucose metabolism in vivo and in isolated hepatocytes in 150-day old rats. Additionally, after body growth, the effects of caloric restriction and refeeding were tested. Adult rats from control （G9） and reduced litters （G3L） did not differ in body and fat weights, glucose tolerance or insulin resistance （insulin-induced hypoglycemia）, or hepatocyte glucose release under basal or gluconeogenic conditions. Caloric restriction （G3R） reduced body and fat weights, decreased glucose decay after insulin injection and decreased hepatocyte gluconeogenic glucose release. Refeeding after caloric restriction reversed these parameters to those of the freely-fed groups （G9 and G3L）. Taken together, these results suggest that the liver glucose metabolism is not programmed by lactational overfeeding, but rather is responsive to the current nutritional condition of the animal.

Mito-specific cascade amplifier sniping metabolism homeostasis for multimodal imaging-guided antitumor bioenergetic therapy

Nicotinamide adenine dinucleotide (NAD+/NADH) pools homeostasis is recognized as an Achilles’ Heel in tumor metabolism reprogramming. However, mitochondria can enable cancer cells to overcome NADH exhaustion by providing NAD+ precursors and/or intermediates, thus promoting their survival rate and potentially driving uncontrollable proliferation. Here, a synergistic intervention NAD+/NADH homeostasis and mitochondrial metabolism strategy with magnetic resonance imaging (MRI)/photoacoustic imaging (PAI) are developed to address grand challenge of metabolic reprogramming for antitumor bioenergetic therapy. A mitochondrial-targeted cascade amplification nanoplatform ([β-MQ]TRL), triggered by NAD(P)H: quinone oxidoreductase-1 (NQO1), can enable a continuous depletion of cytosol NADH until cell death. The end-product, hydrogen peroxide (H_(2)O_(2)), can be further catalytically converted to higher toxic ·OH in proximity to mitochondria based on [β-MQ]TRL mediated Fenton-like reaction, hijacking tumorigenic energy sources and leading to mitochondrial dysfunction. Additionally, the mild thermal ablation enabled by [β-MQ]TRL further amplifies this cascade reaction to effectively prevent tumor metastasis and recurrence. This synchronous intervention strategy with MRI/PAI establishes unprecedented efficiency in antitumor bioenergetic therapy in vivo, which shows excellent promise for clinical application.

Obesity:an evolutionary context

People completely lacking body fat(lipodystrophy/lipoatrophy)and those with severe obesity both show profound metabolic and other health issues.Regulating levels of body fat somewhere between these limits would,therefore,appear to be adaptive.Two different models might be contemplated.More traditional is a set point(SP)where the levels are regulated around a fixed level.Alternatively,dual-intervention point(DIP)is a system that tolerates fairly wide variation but is activated when critically high or low levels are breached.The DIP system seems to fit our experience much better than an SP,and models suggest that it is more likely to have evolved.A DIP system may have evolved because of two contrasting selection pressures.At the lower end,we may have been selected to avoid low levels of fat as a buffer against starvation,to avoid disease-induced anorexia,and to support reproduction.At the upper end,we may have been selected to avoid excess storage because of the elevated risks of predation.This upper limit of control seems to have malfunctioned because some of us deposit large fat stores,with important negative health effects.Why has evolution not protected us against this problem?One possibility is that the protective system slowly fell apart due to random mutations after we dramatically reduced the risk of being predated during our evolutionary history.By chance,it fell apart more in some people than others,and these people are now unable to effectively manage their weight in the face of the modern food glut.To understand the evolutionary context of obesity,it is important to separate the adaptive reason for storing some fat(i.e.the lower intervention point),from the nonadaptive reason for storing lots of fat(a broken upper intervention point).The DIP model has several consequences,showing how we understand the obesity problem and what happens when we attempt to treat it.