Journal: Cell metabolism
Because current therapeutics for obesity are limited and only offer modest improvements, novel interventions are needed. Preventing obesity with time-restricted feeding (TRF; 8-9 hr food access in the active phase) is promising, yet its therapeutic applicability against preexisting obesity, diverse dietary conditions, and less stringent eating patterns is unknown. Here we tested TRF in mice under diverse nutritional challenges. We show that TRF attenuated metabolic diseases arising from a variety of obesogenic diets, and that benefits were proportional to the fasting duration. Furthermore, protective effects were maintained even when TRF was temporarily interrupted by ad libitum access to food during weekends, a regimen particularly relevant to human lifestyle. Finally, TRF stabilized and reversed the progression of metabolic diseases in mice with preexisting obesity and type II diabetes. We establish clinically relevant parameters of TRF for preventing and treating obesity and metabolic disorders, including type II diabetes, hepatic steatosis, and hypercholesterolemia.
Cellular senescence entails a stable cell-cycle arrest and a pro-inflammatory secretory phenotype, which contributes to aging and age-related diseases. Obesity is associated with increased senescent cell burden and neuropsychiatric disorders, including anxiety and depression. To investigate the role of senescence in obesity-related neuropsychiatric dysfunction, we used the INK-ATTAC mouse model, from which p16Ink4a-expressing senescent cells can be eliminated, and senolytic drugs dasatinib and quercetin. We found that obesity results in the accumulation of senescent glial cells in proximity to the lateral ventricle, a region in which adult neurogenesis occurs. Furthermore, senescent glial cells exhibit excessive fat deposits, a phenotype we termed “accumulation of lipids in senescence.” Clearing senescent cells from high fat-fed or leptin receptor-deficient obese mice restored neurogenesis and alleviated anxiety-related behavior. Our study provides proof-of-concept evidence that senescent cells are major contributors to obesity-induced anxiety and that senolytics are a potential new therapeutic avenue for treating neuropsychiatric disorders.
Bread is consumed daily by billions of people, yet evidence regarding its clinical effects is contradicting. Here, we performed a randomized crossover trial of two 1-week-long dietary interventions comprising consumption of either traditionally made sourdough-leavened whole-grain bread or industrially made white bread. We found no significant differential effects of bread type on multiple clinical parameters. The gut microbiota composition remained person specific throughout this trial and was generally resilient to the intervention. We demonstrate statistically significant interpersonal variability in the glycemic response to different bread types, suggesting that the lack of phenotypic difference between the bread types stems from a person-specific effect. We further show that the type of bread that induces the lower glycemic response in each person can be predicted based solely on microbiome data prior to the intervention. Together, we present marked personalization in both bread metabolism and the gut microbiome, suggesting that understanding dietary effects requires integration of person-specific factors.
Post-ingestive signals conveying information about the nutritive properties of food are critical for regulating ingestive behavior. Here, using an auction task concomitant to fMRI scanning, we demonstrate that participants are willing to pay more for fat + carbohydrate compared with equally familiar, liked, and caloric fat or carbohydrate foods and that this potentiated reward is associated with response in areas critical for reward valuation, including the dorsal striatum and mediodorsal thalamus. We also show that individuals are better able to estimate the energy density of fat compared with carbohydrate and fat + carbohydrate foods, an effect associated with functional connectivity between visual (fusiform gyrus) and valuation (ventromedial prefrontal cortex) areas. These results provide the first demonstration that foods high in fat and carbohydrate are, calorie for calorie, valued more than foods containing only fat or carbohydrate and that this effect is associated with greater recruitment of central reward circuits.
In patients with cancer, the wasting syndrome, cachexia, is associated with caloric deficiency. Here, we describe tumor-induced alterations of the host metabolic response to caloric deficiency that cause intratumoral immune suppression. In pre-cachectic mice with transplanted colorectal cancer or autochthonous pancreatic ductal adenocarcinoma (PDA), we find that IL-6 reduces the hepatic ketogenic potential through suppression of PPARalpha, the transcriptional master regulator of ketogenesis. When these mice are challenged with caloric deficiency, the resulting relative hypoketonemia triggers a marked rise in glucocorticoid levels. Multiple intratumoral immune pathways are suppressed by this hormonal stress response. Moreover, administering corticosterone to elevate plasma corticosterone to a level that is lower than that occurring in cachectic mice abolishes the response of mouse PDA to an immunotherapy that has advanced to clinical trials. Therefore, tumor-induced IL-6 impairs the ketogenic response to reduced caloric intake, resulting in a systemic metabolic stress response that blocks anti-cancer immunotherapy.
Calorie restriction (CR) is a dietary intervention with potential benefits for healthspan improvement and lifespan extension. In 53 (34 CR and 19 control) non-obese adults, we tested the hypothesis that energy expenditure (EE) and its endocrine mediators are reduced with a CR diet over 2 years. Approximately 15% CR was achieved over 2 years, resulting in an average 8.7 kg weight loss, whereas controls gained 1.8 kg. In the CR group, EE measured over 24 hr or during sleep was approximately 80-120 kcal/day lower than expected on the basis of weight loss, indicating sustained metabolic adaptation over 2 years. This metabolic adaptation was accompanied by significantly reduced thyroid axis activity and reactive oxygen species (F2-isoprostane) production. Findings from this 2-year CR trial in healthy, non-obese humans provide new evidence of persistent metabolic slowing accompanied by reduced oxidative stress, which supports the rate of living and oxidative damage theories of mammalian aging.
Olfactory inputs help coordinate food appreciation and selection, but their role in systemic physiology and energy balance is poorly understood. Here we demonstrate that mice upon conditional ablation of mature olfactory sensory neurons (OSNs) are resistant to diet-induced obesity accompanied by increased thermogenesis in brown and inguinal fat depots. Acute loss of smell perception after obesity onset not only abrogated further weight gain but also improved fat mass and insulin resistance. Reduced olfactory input stimulates sympathetic nerve activity, resulting in activation of β-adrenergic receptors on white and brown adipocytes to promote lipolysis. Conversely, conditional ablation of the IGF1 receptor in OSNs enhances olfactory performance in mice and leads to increased adiposity and insulin resistance. These findings unravel a new bidirectional function for the olfactory system in controlling energy homeostasis in response to sensory and hormonal signals.
Calorie restriction, without malnutrition, has been shown to increase lifespan and is associated with a shift away from glycolysis toward beta-oxidation. The objective of this study was to mimic this metabolic shift using low-carbohydrate diets and to determine the influence of these diets on longevity and healthspan in mice. C57BL/6 mice were assigned to a ketogenic, low-carbohydrate, or control diet at 12 months of age and were either allowed to live their natural lifespan or tested for physiological function after 1 or 14 months of dietary intervention. The ketogenic diet (KD) significantly increased median lifespan and survival compared to controls. In aged mice, only those consuming a KD displayed preservation of physiological function. The KD increased protein acetylation levels and regulated mTORC1 signaling in a tissue-dependent manner. This study demonstrates that a KD extends longevity and healthspan in mice.
A diurnal rhythm of eating-fasting promotes health, but the eating pattern of humans is rarely assessed. Using a mobile app, we monitored ingestion events in healthy adults with no shift-work for several days. Most subjects ate frequently and erratically throughout wakeful hours, and overnight fasting duration paralleled time in bed. There was a bias toward eating late, with an estimated <25% of calories being consumed before noon and >35% after 6 p.m. “Metabolic jetlag” resulting from weekday/weekend variation in eating pattern akin to travel across time zones was prevalent. The daily intake duration (95% interval) exceeded 14.75 hr for half of the cohort. When overweight individuals with >14 hr eating duration ate for only 10-11 hr daily for 16 weeks assisted by a data visualization (raster plot of dietary intake pattern, “feedogram”) that we developed, they reduced body weight, reported being energetic, and improved sleep. Benefits persisted for a year.
While diet-induced obesity has been exclusively attributed to increased caloric intake from fat, animals fed a high-fat diet (HFD) ad libitum (ad lib) eat frequently throughout day and night, disrupting the normal feeding cycle. To test whether obesity and metabolic diseases result from HFD or disruption of metabolic cycles, we subjected mice to either ad lib or time-restricted feeding (tRF) of a HFD for 8 hr per day. Mice under tRF consume equivalent calories from HFD as those with ad lib access yet are protected against obesity, hyperinsulinemia, hepatic steatosis, and inflammation and have improved motor coordination. The tRF regimen improved CREB, mTOR, and AMPK pathway function and oscillations of the circadian clock and their target genes' expression. These changes in catabolic and anabolic pathways altered liver metabolome and improved nutrient utilization and energy expenditure. We demonstrate in mice that tRF regimen is a nonpharmacological strategy against obesity and associated diseases.