Preclinical and clinical data suggest that body weight (i.e., body fat) is physiologically regulated, and the high heritability seen from monozygotic twin studies suggests a genetic basis to one's defended body weight. Genome-wide association studies have found that a high proportion of variants that correlate with elevated body mass index are expressed in the central nervous system, signifying that the molecular predicates that likely encode for defended body weight will be found in the brain [(1)]. In this context, an individual integrates peripheral signals (e.g., adipokines, myokines, hepatokines) relaying the metabolic state of various tissues to the brain and reacts to maintain relatively stable weight. However, the recent increased prevalence of obesity/overweight reveals that environmental factors must be influencing this system, and why some people are more susceptible to weight gain in a given environment is not fully understood [(2)]. In this issue, Fang et al. [(3)] present an interesting and thorough set of experiments that demonstrate how fat content in diet affects defended body weight in C57BL/6N mice. By changing the macronutrient composition (fat and carbohydrate) of diets and undertaking switches in diet at different ages (young and adult) and for different durations (4, 8, or 24 weeks), as well as putting mice through rounds of weight gain and weight loss (yo-yo dieting), they provide strong evidence that the major driver of defended body weight in these animals is the amount of fat within the diet. The key takeaway message is that higher-fat diets (HFDs, i.e., diets with 45% fat or more) cause defense of an elevated body weight plateau, whereas lower-fat diets (LFDs, i.e., diets with 10% or 25% fat) cause defense of a lower body weight plateau irrespective of the age at which the diets start or their duration. Furthermore, HFD- and LFD-fed animals showed similar physiology to a 16-hour fast, and switching mice back to LFDs after HFD feeding caused rapid and sustained weight loss, with most groups returning to the LFD-fed weight. They suggest that HFDs do not impede normal physiological defense of body weight but rather cause an increase to a new defended body weight. This paradigm shift is subtle but important. Although understanding the mechanisms behind these findings is beyond the scope of the paper, increases in circulating lipids from diets have been causally linked to inflammation of the hypothalamus and may, in part, explain the present findings [(4)]. Of course, humans are exposed to many different variables that are hard to replicate in rodent models. For example, workers are much more sedentary than in the past, numerous excess calories are consumed through simple sugars found in soft drinks, and we undertake numerous activities and hobbies that directly affect our daily metabolic rate. All of these parameters likely contribute to our defended body weight; however, the diet likely remains one of the major modifiable inputs. The search for the molecular underpinnings of defense of body weight will continue to evolve with each new study adding to our overall understanding of this important physiological regulation; however, this study [(3)] clearly demonstrates that fat content seems directly implicated in body weight regulation. The type of food we eat likely influences the system of how our body weight is regulated, and understanding these interactions is crucial. This study suggests that eating diets high in fat may result in the overconsumption of calories leading to elevated body weight. Would you like meringue and gruyère double cream just after having eaten a large fondue? Of course you would. Open access funding provided by Universite de Fribourg. The author declared no conflict of interest.
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Open Access
Apr 28, 2024
Tingting Yu + 2
