Inhibitors of the lipogenic enzyme fatty acid synthase (FASN) have attracted much attention in the last decade as potential targeted cancer therapies. However, little is known about the molecular determinants of cancer cell sensitivity to FASN inhibitors (FASNis), which is a major roadblock to their therapeutic application. Here, we find that pharmacological starvation of endogenously produced FAs is a previously unrecognized metabolic stress that heightens mitochondrial apoptotic priming and favors cell death induction by BH3 mimetic inhibitors. Evaluation of the death decision circuits controlled by the BCL-2 family of proteins revealed that FASN inhibition is accompanied by the upregulation of the pro-death BH3-only proteins BIM, PUMA, and NOXA. Cell death triggered by FASN inhibition, which causally involves a palmitate/NADPH-related redox imbalance, is markedly diminished by concurrent loss of BIM or PUMA, suggesting that FASN activity controls cancer cell survival by fine-tuning the BH3 only proteins-dependent mitochondrial threshold for apoptosis. FASN inhibition results in a heightened mitochondrial apoptosis priming, shifting cells toward a primed-for-death state “addicted” to the anti-apoptotic protein BCL-2. Accordingly, co-administration of a FASNi synergistically augments the apoptosis-inducing activity of the dual BCL-XL/BCL-2 inhibitor ABT-263 (navitoclax) and the BCL-2 specific BH3-mimetic ABT-199 (venetoclax). FASN inhibition, however, fails to sensitize breast cancer cells to MCL-1- and BCL-XL-selective inhibitors such as S63845 and A1331852. A human breast cancer xenograft model evidenced that oral administration of the only clinically available FASNi drastically sensitizes FASN-addicted breast tumors to ineffective single-agents navitoclax and venetoclax in vivo. In summary, a novel FASN-driven facet of the mitochondrial priming mechanistically links the redox-buffering mechanism of FASN activity to the intrinsic apoptotic threshold in breast cancer cells. Combining next-generation FASNis with BCL-2-specific BH3 mimetics that directly activate the apoptotic machinery might generate more potent and longer-lasting antitumor responses in a clinical setting.

Salivary amylase (AMY1) is the most abundant enzyme in human saliva, responsible for the hydrolysis of α-1,4 glycosidic linkages that aids in the digestion of starch. Recently studies have shown that the copy number of AMY1 is associated with obesity; however, the data varies with location. One-third of children are overweight/obese in Alabama. In this study, we aim to determine the relationship between the copy number of AMY1 gene and obesity measurements in children from Alabama. One hundred twenty-seven children aged between 6 to 10 years participated in this study. Anthropometric measurements were measured using WHO recommendations. Genomic DNA was extracted from saliva, and the copy number of the AMY1 gene was estimated by digital PCR. The association between AMY1 copy number and obesity measurements was analyzed by linear regression. The mean AMY1 copy number significantly decreased in overweight/obese (6.21 ± 1.48) compared to normal weight (7.97 ± 2.35) children. AMY1 copy number inversely associated with the obesity measurements. African Americans had a stronger association between low AMY1 copy number and obesity compared to white/European Americans. Our findings suggest that overweight/obese children have a low AMY1 copy number and the effect is more prominent in African Americans.

Parental beliefs, attitudes, and feeding practices play a vital role in childhood obesity. This study aimed to assess parental perceptions, concerns about weight, feeding practices using the Child Feeding Questionnaire (CFQ), and its association with body mass index (BMI) and maternal education in elementary school children. Participants aged 6–10 years (n = 169) were recruited and anthropometric measurements were obtained. Pearson’s correlation and hierarchical linear regression analysis were used to examine the association between BMI z-score and the seven factors of the CFQ. The BMI z-score was significantly associated with parental perceived child weight and concern about child weight. The BMI z-score had a significant negative association with parents pressuring children to eat. Parents of obese children reported significantly higher (p < 0.001) levels of perceived child weight (β = 0.312) and concern (β = 0.320) about their child’s weight compared to the normal weight and overweight groups. Parents of overweight children showed considerably less (β = −0.224; p < 0.005) pressuring towards their children to eat as compared to parents of normal weight children. Additionally, we found that the parental feeding practice (pressure to eat) was only dependent upon maternal education. The path analysis indicates that maternal education has a mediating effect on BMI z-score and pressure to eat is related to BMI z-score through maternal education. The findings demonstrate the association between the parents’ perceptions, concerns, and pressure to eat with BMI z-score of elementary school-aged children. Only the parental feeding practice pressure to eat was dependent upon the maternal education.

Study Objectives: The daily lifestyle behaviors of children have been shown to be associated with obesity. There are limited studies on the association of sleep timing behavior and body mass index (BMI), specifically in elementary school-age children. This study aimed to investigate the relationship between obesity and sleep timing patterns, television exposure time, and dinnertime among elementary school-age children. Methods: Children (n = 169) aged 6 to 10 years who were residents of Alabama were recruited for this study. The questionnaires were used to determine the bedtime, wake-up time, television exposure time, and dinnertime of the participants. The participants were categorized into four groups depending on the bedtime and wake-up time behavior habits: early bed/early wake-up (EE); early bed/late wake-up (EL); late bed/early wake-up (LE); and late bed/late wake-up (LL) time. The BMI z-score, television exposure time, and dinnertime of these groups were compared. Results: The LL group had a significantly higher BMI z-score compared to the EE group. The higher BMI z-score in the LL group may be associated with late bedtime and not late wake-up time. Approximately 71% of children with late bedtime (8:48 PM), 75% of children who watch television for more than 1 hour, and 54% of children who have dinner after 7:00 PM have obesity. Conclusions: Daily behavior habits such as late bedtime, increased television exposure, and late dinnertime are associated with obesity.