By Max Bingham, PhD

Altered brain responses in obese adolescents following the consumption of glucose or fructose in drinks may drive the consumption of more of the monosaccharides and promote further weight gain. This is according to Jastreboff et al. (p. 1929). They suggest that obesity in adolescents may result in altered blood flow patterns in the brain that result in a lack of adequate and appropriate neural regulation of glucose and fructose consumption. The small study compared brain perfusion responses (assessed by functional MRI) following the consumption of 300 mL beverages containing either 75 g of glucose or fructose in lean or obese adolescents. “Striking” differences in brain responses between the groups were observed, according to the authors. Following glucose consumption, the lean adolescents had increased blood perfusion in the brain areas implicated in executive function but no change in the regions vital for homeostatic appetite control. In the obese adolescents, perfusion decreased in the areas involved in executive function but increased in the areas involved in appetite control. Similar differences appeared to occur following fructose consumption. According to the authors, the findings “suggest that obese adolescents may have attenuated executive control response to ingestion of these two simple sugars and diminished capacity to downregulate homeostatic and hedonic regions of the brain, potentially contributing to continued food consumption.” They go on to suggest that the system of reward in obese adolescents may have broken down with the result being that sugar consumption fails to provide an adequate response and therefore may contribute to the motivation to consume more. Commenting more widely on the study, Ania M. Jastreboff stated: “The rise in adolescent obesity has paralleled increases in added-sugar consumption; thus, a better understanding of the biological and behavioral mechanisms contributing to this phenomenon may create opportunities for public health interventions. This study suggests that obesity-related brain adaptations to drinking glucose and fructose may contribute to excessive consumption of these simple sugars, thereby perpetuating obesity.”

Jastreboff et al. Altered brain response to drinking glucose and fructose in obese adolescents. Diabetes 2016;65:1929–1939

Schematic diagram to illustrate altered regional cerebral blood flow response to glucose in lean and obese adolescents.

Schematic diagram to illustrate altered regional cerebral blood flow response to glucose in lean and obese adolescents.

An enzyme called protein arginine methyltransferase 7 (Prmt7) may be a key regulator of skeletal muscle oxidative metabolism, according to a study by Jeong et al. (p. 1868). Specifically, Prmt7 may regulate PGC-1α, a key transcriptional factor involved in a pathway that controls mitochondrial function and oxidative muscle metabolism. Previously, little was known about the role of Prmt7 even though it appears to be highly expressed in skeletal muscle. To unravel its role, the authors first focused on a mouse model deficient in Prmt7. They report that the mice had decreased oxidative metabolism and expression of genes involved in muscle oxidative metabolism, including PGC-1α. The mice also consistently had reduced exercise capacity, reduced energy expenditure, and over time all turned obese. Using a series of experiments in cell cultures based on myoblasts lacking Prmt7, the authors showed the likely role of the enzyme in regulating the PGC-1α/p38MAPK/ATF2 pathway, which is key to skeletal muscle metabolism. Discussing their study, Hyeon-Ju Jeong and Jong-Sun Kang told Diabetes: “Considering the importance of the protective effects of PGC-1α induction against aging-associated muscle atrophy and metabolic diseases, our current study, which provides a new regulatory pathway of PGC-1α, is important. In recent years, various approaches have been taken to develop PGC-1α inducers to mimic exercise effects on skeletal muscle function and metabolic diseases. Prmt7 appears to regulate PGC-1α expression through the p38MAPK/ATF2 pathway, which is the same signaling cascade triggered by exercise-mediated mechanical stretch. Whether or not Prmt7 mediates the beneficial effects of exercise needs to be further investigated. The global PGC-1α induction has adverse effects such as exacerbation of hepatic insulin resistance. Given that Prmt7 expression is highest in skeletal muscle and decreases in aging muscles, modulation of Prmt7 might be an effective target to selectively mimic the exercise effect. Currently we are investigating Prmt7’s role in exercise and other targets of Prmt7 in other energy-expending tissues, such as brown adipose tissue and the heart where Prmt7 is highly expressed.”

Jeong et al. Prmt7 deficiency causes reduced skeletal muscle oxidative metabolism and age-related obesity. Diabetes 2016;65:1868–1882

Prmt7-deficient mice become obese in middle age. Photographs are of 13-month-old female Prmt7+/+ littermates.

Prmt7-deficient mice become obese in middle age. Photographs are of 13-month-old female Prmt7+/+ littermates.

According to an analysis (p. 1988) from The Environmental Determinant of Diabetes in the Young (TEDDY) cohort, greater weight in the first years of life may be associated with a small increased risk of developing islet autoimmunity—the phase preceding the onset of type 1 diabetes. Previously, increased growth rates in early childhood have been suggested to increase the risk of type 1 diabetes and specifically that excessive weight gain (from overfeeding) results in insulin resistance, subsequent β-cell destruction, and autoimmunity. However, data are mixed in terms of support for this so-called “accelerator” hypothesis. Elding Larsson et al. therefore tested the hypothesis that weight and/or height in the first 4 years of life might predict the development of islet autoimmunity and also the progression to type 1 diabetes. They did this using data from the large TEDDY cohort that focuses on children with the increased genetic risk of type 1 diabetes. According to the authors, after 4 years of follow-up so far, 575 children have developed persistent islet autoimmunity, 351 have developed multiple islet autoimmunity, and 169 have progressed to type 1 diabetes. Using Cox proportional hazard analysis, weight z score at 12 months of age predicted islet autoimmunity. However, the effect did not persist at 24 or 36 months. Similar relationships were apparent for multiple islet autoantibodies but no associations were apparent between weight or height and type 1 diabetes. Other statistical analyses confirmed the weak—but statistically significant—relationship. According to the authors, “the relevance of these findings for determining risk of diabetes will require longer follow-up of the cohort and evaluation of additional factors, such as infant feeding and genetic determinants of growth.” According to author Helena Elding Larsson: “The weak effect indicates that growth may not be the primary trigger of islet autoimmunity, but the findings are interesting. Since the children in this cohort are still young, we are aiming to further analyze the association, in relation to additional factors, while the children grow older.”

Elding Larsson et al. Growth and risk for islet autoimmunity and progression to type 1 diabetes in early childhood: The Environmental Determinants of Diabetes in the Young Study. Diabetes 2016;65:1988–1995

A low-fat diet enriched with n-3 fatty acids early in life may have a significant impact on metabolic outcomes later in life when exposed to a high-fat diet and according to Demizieux et al. (p. 1824), the endocannabinoid system, which is central to energy homeostasis, may be key to determining such outcomes. In obesity, the system is overactive but may be controllable by reducing levels of endogenous cannabinoid receptor agonists. These are derived from arachidonic acid, which in turn can be synthesized from the n-6 fatty acid, linoleic acid. In theory, substituting n-6 for the n-3 fatty acid, α-linolenic acid, might result in reductions in endocannabinoid signaling. To test this hypothesis, the authors exposed three groups of mice to a low-fat diet enriched with lard alone or in combination with α-linolenic acid or linoleic acid for 10 weeks, followed by 10 weeks on a 30% lard only high-fat diet. They then assessed a variety of parameters relating to the endocannabinoid system and metabolism at the end of each of the 10-week periods. The early diet enriched with α-linolenic acid induced a marked decrease in liver endocannabinoid levels as well as changes in hepatic expression of a variety of enzymes involved in carbohydrate and lipid metabolism. Some gene expression changes also persisted on the high-fat diet and were associated with improved glycemic control. Confirming the observations, the authors noted that the same effects were not observed in mice that received the early diet enriched with linoleic acid, and that mice genetically modified to synthesize high levels of n-3 fatty acids in tissues also had reduced levels of liver endocannabinoids. The corresponding authors of the study, Vincenzo Di Marzo and Pascal Degrace, said: “This study may help explain why diets with unbalanced fatty acid contents early in life might impair the capability of coping with the negative effect of high-fat diets on insulin sensitivity later in life, thus predisposing to type 2 diabetes.”

Demizieux et al. Early low-fat diet enriched with linolenic acid reduces liver endocannabinoid tone and improves late glycemic control after a high-fat diet challenge in mice. Diabetes 2016;65:1824–1837