Highlights • This manuscript provides an overview of what is known about the role of the gut microbiota in rodent and human energy homeostasis. • This manuscript reviews the differences between ...humans and rodents that may affect the ability to extrapolate conclusions from one order of mammals to the other. • This manuscript suggests future directions of research into the human microbiota that are informed by rodent studies.
A low-error 16S ribosomal RNA amplicon sequencing method, in combination with whole-genome sequencing of >500 cultured isolates, was used to characterize bacterial strain composition in the fecal ...microbiota of 37 U.S. adults sampled for up to 5 years. Microbiota stability followed a power-law function, which when extrapolated suggests that most strains in an individual are residents for decades. Shared strains were recovered from family members but not from unrelated individuals. Sampling of individuals who consumed a monotonous liquid diet for up to 32 weeks indicated that changes in strain composition were better predicted by changes in weight than by differences in sampling interval. This combination of stability and responsiveness to physiologic change confirms the potential of the gut microbiota as a diagnostic tool and therapeutic target.
Very low-carbohydrate, high-fat ketogenic diets (KDs) induce a pronounced shift in metabolic fuel utilization that elevates circulating ketone bodies; however, the consequences of these compounds for ...host-microbiome interactions remain unknown. Here, we show that KDs alter the human and mouse gut microbiota in a manner distinct from high-fat diets (HFDs). Metagenomic and metabolomic analyses of stool samples from an 8-week inpatient study revealed marked shifts in gut microbial community structure and function during the KD. Gradient diet experiments in mice confirmed the unique impact of KDs relative to HFDs with a reproducible depletion of bifidobacteria. In vitro and in vivo experiments showed that ketone bodies selectively inhibited bifidobacterial growth. Finally, mono-colonizations and human microbiome transplantations into germ-free mice revealed that the KD-associated gut microbiota reduces the levels of intestinal pro-inflammatory Th17 cells. Together, these results highlight the importance of trans-kingdom chemical dialogs for mediating the host response to dietary interventions.
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•Ketogenic diets (KDs) alter the gut microbiota in a manner distinct from high-fat diets•Gut microbial shifts on KDs are driven in part through host production of ketone bodies•β-hydroxybutyrate selectively inhibits bifidobacterial growth•The KD-associated gut microbiota reduces levels of intestinal Th17 cells
Ketogenic diets differ from high fat diets in that they alter the gut microbiome to affect the level of gut Th17 cells.
Objective
To test three proposed models for adaptive thermogenesis in compartments of energy expenditure following different degrees of weight loss. Specifically, (1) there is no adaptive ...thermogenesis constant relationship of energy expenditure (EE) to metabolic mass. (2) There is a fixed degree of adaptive thermogenesis once fat stores are below a “threshold.” (3) The degree of adaptive thermogenesis is proportional to weight loss.
Methods
The relationship between weight loss and EE was examined in 17 inpatient subjects with stable weight and obesity studied at usual weight and again following a 10% and a 20% weight loss.
Results
Following initial weight loss (10%), resting (REE) and non‐resting (NREE) EE were significantly below those predicted on the basis of the amount and composition of weight lost. Further reductions below predicted values of NREE but not REE occurred following an additional 10% weight loss. Changes in body weight, composition, and/or energy stores were significantly correlated with changes in EE.
Conclusions
All models are applicable to the decline in EE following weight loss. The disproportionate decline in REE is consistent with a threshold model (no change with further weight loss) while the disproportionate decline in NREE is largely reflective of the degree of weight loss.
Because leptin reduces food intake and body weight, the coexistence of elevated leptin levels with obesity is widely interpreted as evidence of ‘leptin resistance.’ Indeed, obesity promotes a number ...of cellular processes that attenuate leptin signaling (referred to here as ‘cellular leptin resistance’) and amplify the extent of weight gain induced by genetic and environmental factors. As commonly used, however, the term ‘leptin resistance’ embraces a range of phenomena that are distinct in underlying mechanisms and pathophysiological implications. Moreover, the induction of cellular leptin resistance by obesity complicates efforts to distinguish the mechanisms that predispose to weight gain from those that result from it. We suggest a framework for approaching these issues and important avenues for future investigation.
Abstract
Obesity is among the most common and costly chronic disorders worldwide. Estimates suggest that in the United States obesity affects one-third of adults, accounts for up to one-third of ...total mortality, is concentrated among lower income groups, and increasingly affects children as well as adults. A lack of effective options for long-term weight reduction magnifies the enormity of this problem; individuals who successfully complete behavioral and dietary weight-loss programs eventually regain most of the lost weight. We included evidence from basic science, clinical, and epidemiological literature to assess current knowledge regarding mechanisms underlying excess body-fat accumulation, the biological defense of excess fat mass, and the tendency for lost weight to be regained. A major area of emphasis is the science of energy homeostasis, the biological process that maintains weight stability by actively matching energy intake to energy expenditure over time. Growing evidence suggests that obesity is a disorder of the energy homeostasis system, rather than simply arising from the passive accumulation of excess weight. We need to elucidate the mechanisms underlying this “upward setting” or “resetting” of the defended level of body-fat mass, whether inherited or acquired. The ongoing study of how genetic, developmental, and environmental forces affect the energy homeostasis system will help us better understand these mechanisms and are therefore a major focus of this statement. The scientific goal is to elucidate obesity pathogenesis so as to better inform treatment, public policy, advocacy, and awareness of obesity in ways that ultimately diminish its public health and economic consequences.
This Scientific Statement focuses on factors for which compelling evidence exists that implicates them in the pathogenesis of either the accumulation or maintenance of excess body fat mass.
The carbohydrate-insulin model of obesity posits that habitual consumption of a high-carbohydrate diet sequesters fat within adipose tissue because of hyperinsulinemia and results in adaptive ...suppression of energy expenditure (EE). Therefore, isocaloric exchange of dietary carbohydrate for fat is predicted to result in increased EE, increased fat oxidation, and loss of body fat. In contrast, a more conventional view that "a calorie is a calorie" predicts that isocaloric variations in dietary carbohydrate and fat will have no physiologically important effects on EE or body fat.
We investigated whether an isocaloric low-carbohydrate ketogenic diet (KD) is associated with changes in EE, respiratory quotient (RQ), and body composition.
Seventeen overweight or obese men were admitted to metabolic wards, where they consumed a high-carbohydrate baseline diet (BD) for 4 wk followed by 4 wk of an isocaloric KD with clamped protein. Subjects spent 2 consecutive days each week residing in metabolic chambers to measure changes in EE (EEchamber), sleeping EE (SEE), and RQ. Body composition changes were measured by dual-energy X-ray absorptiometry. Average EE during the final 2 wk of the BD and KD periods was measured by doubly labeled water (EEDLW).
Subjects lost weight and body fat throughout the study corresponding to an overall negative energy balance of ∼300 kcal/d. Compared with BD, the KD coincided with increased EEchamber (57 ± 13 kcal/d, P = 0.0004) and SEE (89 ± 14 kcal/d, P < 0.0001) and decreased RQ (-0.111 ± 0.003, P < 0.0001). EEDLW increased by 151 ± 63 kcal/d (P = 0.03). Body fat loss slowed during the KD and coincided with increased protein utilization and loss of fat-free mass.
The isocaloric KD was not accompanied by increased body fat loss but was associated with relatively small increases in EE that were near the limits of detection with the use of state-of-the-art technology. This trial was registered at clinicaltrials.gov as NCT01967563.
BACKGROUND: After weight loss, total energy expenditure--in particular, energy expenditure at low levels of physical activity--is lower than predicted by actual changes in body weight and ...composition. An important clinical issue is whether this reduction, which predisposes to weight regain, persists over time. OBJECTIVE: We aimed to determine whether this disproportionate reduction in energy expenditure persists in persons who have maintained a body-weight reduction of greater-than-or-equal10% for >1 y. DESIGN: Seven trios of sex- and weight-matched subjects were studied in an in-patient setting while receiving a weight-maintaining liquid formula diet of identical composition. Each trio consisted of a subject at usual weight (Wtinitial), a subject maintaining a weight reduction of greater-than-or-equal10% after recent (5-8 wk) completion of weight loss (Wtloss₋recent), and a subject who had maintained a documented reduction in body weight of >10% for >1 y (Wtloss₋sustained). Twenty-four-hour total energy expenditure (TEE) was assessed by precise titration of fed calories of a liquid formula diet necessary to maintain body weight. Resting energy expenditure (REE) and the thermic effect of feeding (TEF) were measured by indirect calorimetry. Nonresting energy expenditure (NREE) was calculated as NREE = TEE - (REE +TEF). RESULTS: TEE, NREE, and (to a lesser extent) REE were significantly lower in the Wtloss₋sustained and Wtloss₋recent groups than in the Wtinitial group. Differences from the Wtinitial group in energy expenditure were qualitatively and quantitatively similar after recent and sustained weight loss. CONCLUSION: Declines in energy expenditure favoring the regain of lost weight persist well beyond the period of dynamic weight loss.
Common polymorphisms in the first intron of FTO are associated with increased body weight in adults. Previous studies have suggested that a CUX1-regulatory element within the implicated FTO region ...controls expression of FTO and the nearby ciliary gene, RPGRIP1L. Given the role of ciliary genes in energy homeostasis, we hypothesized that mice hypomorphic for Rpgrip1l would display increased adiposity. We find that Rpgrip1l+/− mice are hyperphagic and fatter, and display diminished suppression of food intake in response to leptin administration. In the hypothalamus of Rpgrip1l+/− mice, and in human fibroblasts with hypomorphic mutations in RPGRIP1L, the number of AcIII-positive cilia is diminished, accompanied by impaired convening of the leptin receptor to the vicinity of the cilium, and diminished pStat3 in response to leptin. These findings suggest that RPGRIP1L may be partly or exclusively responsible for the obesity susceptibility signal at the FTO locus.
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•Mice heterozygous for a null Rpgrip1l allele are fatter than wild-type controls•Leptin signaling is diminished in the hypothalami of Rpgrip1l+/− mice•The localization of the leptin receptor is perturbed in Rpgrip1l+/− mice•RPGRIP1L may account for part or all of the association of the FTO locus with BMI
Common polymorphisms in the first intron of the Fat Mass and Obesity-Associated (FTO) gene are linked with increased body weight in adults. Stratigopoulos et al. show that the nearby ciliary gene, RPGRIP1L, could be responsible for the obesity susceptibility signal at the FTO locus.
Mammals regulate fat mass so that increases or reductions in adipose tissue mass activate responses that favor return to one’s previous weight. A reduction in fat mass activates a system that ...increases food intake and reduces energy expenditure; conversely, overfeeding and rapid adipose tissue expansion reduces food intake and increases energy expenditure. With the identification of leptin nearly two decades ago, the central circuit that defends against reductions in body fat was revealed. However, the systems that defend against rapid expansion of fat mass remain largely unknown. Here we review the physiology of the overfed state and evidence for a distinct regulatory system, which unlike the leptin-mediated system, we propose primarily measures a functional aspect of adipose tissue and not total mass per se.
Body fat is regulated so that weight changes activate responses that favor restoration of previous body fat, with leptin regulating the response to reduced fat. Ravussin et al. review the physiology of the overfed state and propose the existence of a catabolic signal maintaining energy homeostasis in response to overfeeding.
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