Maintenance of a reduced body weight is accompanied by a decrease in energy expenditure beyond that accounted for by reduced body mass and composition, as well as by an increased drive to eat. These effects appear to be due— in part—to reductions in circulating leptin concentrations due to loss of body fat. Gut microbiota have been implicated in the regulation of body weight. The effects of weight loss on qualitative aspects of gut microbiota have been studied in humans and mice, but these studies have been confounded by concurrent changes in diet composition, which influence microbial community composition. We studied the impact of 20% weight loss on the microbiota of diet-induced obese (DIO: 60% calories fat) mice on a high-fat diet (HFD). Weight-reduced DIO (DIO-WR) mice had the same body weight and composition as control (CON) adlibitum (AL) fed mice being fed a control diet (10% calories fat), allowing a direct comparison of diet and weight-perturbation effects. Microbial community composition was assessed by pyrosequencing 16S rRNA genes derived from the ceca of sacrificed animals. There was a strong effect of diet composition on the diversity and composition of the microbiota. The relative abundance of specific members of the microbiota was correlated with circulating leptin concentrations and gene expression levels of inflammation markers in subcutaneous white adipose tissue in all mice. Together, these results suggest that both host adiposity and diet composition impact microbiota composition, possibly through leptin-mediated regulation of mucus production and/or inflammatory processes that alter the gut habitat.

The circadian clock in peripheral tissues can be entrained by restricted feeding (RF), a regimen that restricts the duration of food availability with no calorie restriction (CR). However, it is not known whether RF can delay the occurrence of age-associated changes similar to CR. We measured circadian expression of clock genes, disease marker genes, metabolic factors and inflammatory and allergy markers in mouse serum, liver, jejunum and white adipose tissue (WAT) after long-term RF of 4 months. We found that circadian rhythmicity is more robust and is phase advanced in most of the genes and proteins tested under RF. In addition, average daily levels of some disease and inflammatory markers were reduced under RF, including liver Il-6 mRNA, tumour necrosis factor (TNF)-α and nuclear factor κB (NF-κB) protein; jejunum Arginase, Afp, Gadd45β, Il-1α and Il-1β mRNA, and interleukin (IL)-6 and TNF-α protein and WAT Il-6, Il-1β, Tnfα and Nfκb mRNA. In contrast, the anti-inflammatory cytokine Il-10 mRNA increased in the liver and jejunum. Our results suggest that RF may share some benefits with those of CR. As RF is a less harsh regimen to follow than CR, the data suggest it could be proposed for individuals seeking to improve their health.

We studied temporal partitioning between two spiny mouse species that coexist in hot rocky deserts in the Middle East: nocturnal common spiny mice (Acomys cahirinus) and diurnally active golden spiny mice (A. russatus). Although A. russatus is diurnally active, it retains the physical activity and body temperature rhythms of nocturnal mammals. We studied the two species in four 1000‐m2 enclosures at Ein Gedi, Israel: two experimental enclosures with A. russatus kept alone, and two controls with individuals of both species kept together. We monitored activity with Sherman traps and by studying foraging microhabitat use and efficiency using giving‐up densities (GUDs) in food trays. The trays contained broken sunflower seeds mixed in local soil and placed in three microhabitats: under boulders, between boulders, and in the open. Trapping revealed that, in the absence of A. cahirinus, the usually diurnal A. russatus was active both day and night. However, during the day A. russatus still foraged in significantly more patches and to significantly lower GUDs than during the night. Both species, but in particular A. russatus, preferred to forage in the boulder habitat. Spiny mice foraged in the same number of trays in the under‐ and between‐boulder microhabitats, but to lower GUDs in the under‐boulder microhabitat, both during the day (A. russatus) and during the night (both species). The nocturnal A. cahirinus exploited more patches with greater efficiency than did A. russatus either during the day or during the night. This result suggests that foraging trade‐offs that give each species a competitive advantage along some portion of the resource axis cannot be a mechanism of nocturnal coexistence between the two species. Perhaps this is why A. russatus resorts to diurnal activity in this hot rocky desert and why the otherwise rare mechanism of temporal partitioning occurs for these species.

Objective To compare, in mice, the accuracy of estimates of energy expenditure using an energy balance technique (TEEbal : food energy intake and body composition change) versus indirect calorimetry (TEEIC). Subjects In 32 male C57BL/6J mice energy expenditure was estimated using an energy balance (caloric intake minus change in body energy stores) method over a 37 day period. Energy expenditure was also measured in the same animals by indirect calorimetry. These measures were compared. Results The two methods were highly correlated (r2 = 0.87: TEEbal = 1.07 * TEEIC − 0.22, p < 0.0001). By Bland-Altman analysis, TEEbal estimates were slightly higher (4.6±1.5%; p < 0.05) than TEEIC estimates (Bias = 0.55 kcal/24h). Conclusion TEEbal can be performed in “home cages” and provides an accurate integrated long-term measurement of energy expenditure while minimizing potentially confounding stress that may accompany the use of indirect calorimetry systems. The technique can also be used to assess long term energy intake.

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Golden spiny mice, which inhabit rocky deserts and do not store food, must therefore employ physiological means to cope with periods of food shortage. Here we studied the physiological means used by golden spiny mice for conserving energy during food restriction and refeeding and the mechanism by which food consumption may influence thermoregulatory mechanisms and metabolic rate. As comparison, we studied the response to food restriction of another rocky desert rodent, Wagner's gerbil, which accumulates large seed caches. Ten out of 12 food-restricted spiny mice (resistant) were able to defend their body mass after an initial decrease, as opposed to Wagner's gerbils (n = 6). Two of the spiny mice (nonresistant) kept losing weight, and their food restriction was halted. In four resistant and two nonresistant spiny mice, we measured heart rate, body temperature, and oxygen consumption during food restriction. The resistant spiny mice significantly (P < 0.05) reduced energy expenditure and entered daily torpor. The nonresistant spiny mice did not reduce their energy expenditure. The gerbils' response to food restriction was similar to that of the nonresistant spiny mice. Resistant spiny mice leptin levels dropped significantly (n = 6, P < 0.05) after 24 h of food restriction, and continued to decrease throughout food restriction, as did body fat. During refeeding, although the golden spiny mice gained fat, leptin levels were not correlated with body mass (r(2) = 0.014). It is possible that this low correlation allows them to continue eating and accumulate fat when food is plentiful.

Leibel RL. Effects of chronic weight perturbation on energy homeostasis and brain structure in mice. Am J Physiol Regul Integr Comp Physiol 300: R1352-R1362, 2011. First published March 16, 2011 doi:10.1152/ajpregu.00429.2010.-Maintenance of reduced body weight in lean and obese human subjects results in the persistent decrease in energy expenditure below what can be accounted for by changes in body mass and composition. Genetic and developmental factors may determine a central nervous system (CNS)-mediated minimum threshold of somatic energy stores below which behavioral and metabolic compensations for weight loss are invoked. A critical question is whether this threshold can be altered by environmental influences and by what mechanisms such alterations might be achieved. We examined the bioenergetic, behavioral, and CNS structural responses to weight reduction of diet-induced obese (DIO) and never-obese (CON) C57BL/6J male mice. We found that weightreduced (WR) DIO-WR and CON-WR animals showed reductions in energy expenditure, adjusted for body mass and composition, comparable (Ϫ10 -15%) to those seen in human subjects. The proportion of excitatory synapses on arcuate nucleus proopiomelanocortin neurons was decreased by ϳ50% in both DIO-WR and CON-WR mice. These data suggest that prolonged maintenance of an elevated body weight (fat) alters energy homeostatic systems to defend a higher level of body fat. The synaptic changes could provide a neural substrate for the disproportionate decline in energy expenditure in weight-reduced individuals. This response to chronic weight elevation may also occur in humans. The mouse model described here could help to identify the molecular/cellular mechanisms underlying both the defense mechanisms against sustained weight loss and the upward resetting of those mechanisms following sustained weight gain. obesity; set point; energy metabolism; POMC neurons LONG-TERM MAINTENANCE OF EVEN modest reductions in body weight ameliorates or eliminates many of the comorbidities of obesity (10). The recidivism rate to obesity in formerly obese individuals is 75-85% (59), reflecting the potent metabolic and environmental pressures opposing long-term maintenance of a reduced body weight. We have previously shown that the maintenance of a 10% or greater reduction in body weight in both lean and obese humans is associated with a decrease in energy expenditure (EE) that is 15-20% below what can be accounted for by changes in body mass and body composition.This adaptive thermogenesis does not abate over time (46) and predominantly reflects increased mechanical work efficiency of skeletal muscle, decreased circulating concentrations of bioactive thyroid hormones, and reduced sympathetic autonomic nervous system tone (2,32,46,54).Leptin is an adipocyte-derived hormone whose circulating plasma concentrations are correlated with fat stores at usual (stable) body weight but which rapidly decline during food restriction and/or fasting (1, 52). We have proposed that central nervous system (CNS) en...

Metformin is a commonly-used treatment for type 2 diabetes, whose mechanism of action has been linked, in part, to activation of AMP-activated protein kinase (AMPK). However, little is known regarding its effect on circadian rhythms. Our aim was to evaluate the effect of metformin administration on metabolism, locomotor activity and circadian rhythms. We tested the effect of metformin treatment in the liver and muscle of young lean, healthy mice, as obesity and diabetes disrupt circadian rhythms. Metformin led to increased leptin and decreased glucagon levels. The effect of metformin on liver and muscle metabolism was similar leading to AMPK activation either by liver kinase B1 (LKB1) and/or other kinases in the muscle. AMPK activation resulted in the inhibition of acetyl CoA carboxylase (ACC), the rate limiting enzyme in fatty acid synthesis. Metformin also led to the activation of liver casein kinase I α (CKIα) and muscle CKIε, known modulators of the positive loop of the circadian clock. This effect was mainly of phase advances in the liver and phase delays in the muscle in clock and metabolic genes and/or protein expression. In conclusion, our results demonstrate the differential effects of metformin in the liver and muscle and the critical role the circadian clock has in orchestrating metabolic processes.