Redoxoma Highlights

The ideal type of diet is a long-sought goal that has not been fulfilled so far, both for preventive as well as therapeutic purposes. At the same time, caloric restriction has been well demonstrated to afford increase in lifespan in several species. Intermittent feeding has been used as a substitute for caloric restriction both by overweight or obese individuals (frequently without medical supervision) or, experimentally, as a mechanistical tool to understand the physiology of lifespan extension. These intermittently-fed animals, indeed display decreased body mass, but surprisingly overall caloric intake is similar to that of ad libitum-fed animals. Work performed by the CEPID-Redoxoma group led by Kowaltowski and collaborators provided a detailed analysis to unravel this paradox. The authors showed that intermittent diets, alternating 24-hour fasting and feeding periods, promote lowed body mass, while associating with overeating during fed periods. Such lower energetic efficiency of diets was linked to increased lipid oxidation during fasting days and higher metabolic rates during fed days. Mitochondrial bioenergetics was unaltered, and the lower energy conversion was not due to uncoupling of electron transport chain. Importantly, hypothalamic energy metabolism control was significantly altered, increasing hunger and energy expenditure. Evidence was provided that intermittently fasted animals present higher levels of the orexigenic hypothalamic mediators AGRP and NPY both when fed and fasted, leading to overeating when food is available. High levels of lipid oxidation on fasting days, associated with higher catabolic rates during feeding days, promote lower energy conversion efficiency leading to lower body mass in intermittent feeding. This work clarifies mechanistical pathways involved in feeding and metabolic rates after caloric restriction. While it is premature to associate these findings to human conditions, the results implicate very distinct bioenergetic consequences arising from different restrictive dietary interventions.

Francisco RM Laurindo
Editor, Redoxoma Newsletter
Instituto do Coração
Faculdade de Medicina, Universidade de São Paulo

Comment on:

• Chausse B, Solon C, Caldeira da Silva CC, Masselli Dos Reis IG, Manchado-Gobatto FB, Gobatto CA, Velloso LA, Kowaltowski AJ. Intermittent fasting induces hypothalamic modifications resulting in low feeding efficiency, low body mass and overeating. Endocrinology. 2014 Jul;155(7):2456-66.

Redoxoma Highlights

Excited species such as singlet molecular oxygen [O₂(¹Δ_g)] and triplet carbonyls are a less understood subgroup of oxygen-derived oxidants in BioMedicine. Their generation has been associated to the detection of ultraweak chemiluminescence in mammalian tissues and there is emerging evidence for their roles in pathophysiological situations. However, pathways accounting for their generation in vivo have remained obscure, limiting the assessment of their biological roles. In vitro, excited species arise from photochemical processes involving direct excitation by light. However, atypical photochemical processes not involving photoexcitation have been proposed a number of years ago in pioneer work led, in particular, by Prof. Giuseppe Cilento, from the Chemistry Institute, University of São Paulo. Such “photochemistry in the dark” include reactions associated with dismutation of alkoxyl or alkylperoxyl radicals, pathways linked to dioxetane/oxetane decay and, particularly, triplet carbonyls arising during lipid peroxidation. Importantly, triplet carbonyls can arise from enzymatic peroxidation, raising the possibility of regulated generation of excited species in vivo. Recent work from the CEPID-Redoxoma group led by DiMascio and collaborators provided a significant step ahead to clarify this question. For that, they used chemiluminescescence, spin-trapping and mass spectrometry techniques with chemical trapping of ¹⁸O-labelled singlet molecular oxygen. The results of these studies provided unequivocal evidence that singlet molecular oxygen is generated by energy transfer from chemically as well as enzymatically-produced triplet acetone to ground state triplet molecular oxygen in aqueous phase. Thus, enzyme-catalyzed triplet carbonyls may be a source of singlet molecular oxygen even in the absence of photoexcitation. These reactions may be especially relevant in lipid environments such as membranes, given that molecular oxygen is 10 times more soluble in membranes than aqueous solution. Moreover, triplet carbonyls are well-known products of polyunsaturated fatty acid oxidation. Together, this provides a novel plausible biological route for implicating singlet molecular oxygen generation and reactivity in membrane damage and potentially in other lipid-associated diseases such as atherosclerosis and neurodegeneration.

Francisco RM Laurindo
Editor, Redoxoma Newsletter
Instituto do Coração
Faculdade de Medicina, Universidade de São Paulo

Comment on:

• Mano CM, Prado FM, Massari J, Ronsein GE, Martinez GR, Miyamoto S, Cadet J, Sies H, Medeiros MH, Bechara EJ, Di Mascio P. Excited singlet molecular O₂(¹Δg) is generated enzymatically from excited carbonyls in the dark. Sci Rep. 2014 Aug 4;4:5938.
  http://dx.doi.org/10.1038/srep05938