Obesity is a growing threat worldwide, and the prevalence has risen dramatically over the last decade. Several studies have shown that early life exposures are important in promoting adult obesity (1,2,3). The period from conception to birth is a time of rapid growth, cellular replication and differentiation, and functional maturation of organ systems. These processes are very sensitive to alterations of the nutritional milieu. A large number of studies have linked low birth weight to the later development of central adiposity (4). The landmark cohort study of 300,000 men by Ravelli et al. (5) showed that exposure to the Dutch famine of 1944–1945 during the first half of pregnancy resulted in low birth weight and was associated with significantly higher obesity rates at age 19. The mechanisms underlying the association between low birth weight and the later development of obesity are unclear. Maternal malnutrition in the rat during pregnancy and lactation results in fetal growth retardation and offspring exhibit increased appetite and rapid catch-up growth, resulting in relative obesity and increased body weight, percentage body fat, and plasma leptin levels (4,6). Similarly, maternal food restriction in a mouse model also results in the development of obesity in the offspring (7,8). Data from a number of recent studies support a role for perinatal leptin levels as modulators of the development of adult obesity (9). Mounting evidence supports an interaction between circadian rhythms, sleep, and clock-related gene expression with obesity and metabolic syndrome. Mice with disruptions in core clock genes such as Clock and Bmal1 have many hallmarks of human metabolic syndrome, including alterations in glucose homeostasis and insulin signaling, as well as obesity (10,11). In addition, mice deficient in either Clock (11) or Per2 (12) demonstrate altered patterns of food intake (increased food intake during the light period) and associated obesity. In at least one case, this pathology is associated with peripheral, rather than central, clock function. When Clock was deleted in peripheral tissues (liver and skeletal muscle), but left intact in the central nervous system, obesity did not develop. However, as in previous studies, there was evidence of impaired insulin secretion coupled with increased insulin sensitivity (13). Further, in normal mice, the timing of food intake has been demonstrated to be a critical factor in the development of obesity, with an increase risk for obesity when nocturnal animals are fed high-fat (HF) diet during the light cycle (14). Thus, the timing of food intake, as well as its metabolism, is intricately linked with circadian clock function. The converse relationship has shown to hold as well. Ingestion of HF diet or obesity can change expression of clock genes and activity and sleep patterns. In genetically obese or diet-induced obese animals, expression of core clock genes was altered both peripherally [liver and kidney (15)], as well as in the brainstem (16). Additionally, functional deficits have been observed. Administration of a HF diet has been shown to decrease an animal’s ability to synchronize to light cues (17), whereas genetically obese db/db mice were shown to have a disrupted sleep cycle (18). The paper in this issue of Endocrinology by Sutton et al. (19) adds a new twist to this story by examining the impact of maternal malnutrition on both metabolic and circadian endpoints. In offspring from dams fed a protein deficient diet, obesity and insulin resistance developed, as well as arrhythmic expression of circadian oscillator genes. Importantly, the alterations in circadian gene expression were noted prior to the onset of obesity, suggesting some level of causation. Numerous studies examining the effects of prenatal programming have noted important sex differences, and this paper showed that female mice are less susceptible to the locomotor disruptions. One intriguing finding was that the alterations in circadian related genes were evident in the liver and cortex; however, there were no observed changes in the medial basal hypothalamus, a region that contains the superchiasmatic nucleus, the body’s central circadian pacemaker. This may be a technical issue because the superchiasmatic nucleus is only a few thousand cells within the medial basal hypothalamic region; it remains possible that true differences went undetected in the larger dissection. Future studies with improved anatomical resolution may resolve this issue. The present paper provides an essential piece to the puzzle by demonstrating that clock dysfunction can precede obesity in at least one animal model of obesity. Determining to what extent these findings apply to other models will be critical, and will further inform the increasingly relevant question of how disrupted clock function can predispose for disease.
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Sep 8, 2018
Aline R Abreu + 3
Open Access
