Breaking the intergenerational cycle of obesity with SIRT1

A wealth of evidence from epidemiological studies and animal models shows that maternal overnutrition programmes the development of obesity and metabolic disorders in offspring. These effects are long term and transgenerational such that subsequent generations are at an increased risk of developing obesity and its associated metabolic disorders, thus creating an intergenerational cycle of obesity. In light of the current obesity epidemic where obesity rates are still on the rise, there is no doubt that identifying and developing intervention strategies to break this intergenerational cycle of obesity is of the utmost importance.

Investigations into factors that contribute to the programming of obesity have led to the discovery of several molecular targets, one of which is sirtuin 1 (SIRT1), a member of the sirtuin family. SIRT1 is a nicotinamide adenine dinucleotide (NAD⁺)‐dependent enzyme that catalyses NAD⁺ to 2′‐O‐acetyl‐ADP‐ribose and nicotinamide; it is involved in a variety of cellular processes, including those related to ageing, metabolism and inflammation. SIRT1 levels are increased following caloric restriction and are reduced in obesity, thus suggesting its role as a metabolic regulator. Recent research has also shown that maternal diet can impact on offspring SIRT1 expression where maternal high‐fat diet reduces SIRT1 expression in the offspring's kidney after birth (Nguyen et al. 2017). Given that maternal high‐fat diet programmes offspring obesity, this prompts two questions: (1) does maternal high‐fat diet reduce SIRT1 expression in the offspring, resulting in long term metabolic disorders, or (2) is offspring SIRT1 reduced as a result of offspring obesity following maternal high‐fat feeding?

In this issue of The Journal of Physiology, Nguyen et al. asked whether SIRT1 is causal to the development of metabolic disorders in offspring of high fat‐fed dams (Nguyen et al. 2019). To test this, they genetically overexpressed SIRT1 in offspring of high fat‐fed dams such that the increase in SIRT1 precedes any metabolic changes as a result of maternal high‐fat feeding. To generate this mouse model, Nguyen et al. crossed SIRT1‐overexpressing transgenic sires with high fat‐fed or chow‐fed dams and examined metabolic outcomes of the male offspring, which either overexpress SIRT1 or not. This yielded four groups: (1) wild‐type offspring of chow‐fed dams, (2) wild‐type offspring of high fat‐fed dams, (3) SIRT1‐overexpressing offspring of chow‐fed dams, and (4) SIRT1‐overexpressing offspring of high fat‐fed dams. If SIRT1 is causal to metabolic disorders in offspring of high fat‐fed dams, then SIRT1 overexpression would ameliorate the negative metabolic outcomes in these offspring.

Indeed, Nguyen et al. showed that overexpression of SIRT1 in male offspring of high fat‐fed dams protected the offspring against negative metabolic consequences of maternal high‐fat feeding (Nguyen et al. 2019). Specifically, they found that SIRT1 overexpression corrected maternal high fat diet‐induced hyperleptinaemia, glucose intolerance, liver lipogenesis, inflammation and adiposity when compared to wild‐type offspring of high fat‐fed dams. Consistent with the improved metabolic profiles of SIRT1‐overexpressing offspring of high fat‐fed dams, SIRT1 overexpression increased peroxisome proliferator‐activated receptor γ mRNA, Akt protein and activity, and reduced fatty acid synthase and carbohydrate response element binding protein expression in the liver, suggesting increased insulin sensitivity and reduced liver lipogenesis. Compared to wild‐type offspring of high fat‐fed dams, the authors also observed increased endogenous antioxidants (glutathione peroxidase 1 and catalase) in the liver of SIRT1‐overexpressing offspring of high fat‐fed dams, indicating a possible reduction in obesity‐induced inflammation. In the epididymal adipose tissue, SIRT1 overexpression reduced lipogenic genes such as sterol regulatory element‐binding protein 1c expression, supporting the reduced epididymal fat mass in SIRT1‐overexpressing offspring of high fat‐fed dams. These findings are consistent with the role of SIRT1 in metabolism, but importantly, add to the literature demonstrating that a maternal high‐fat diet can negatively impact on offspring SIRT1 expression, which can predispose the offspring to long term metabolic disorders.

This overexpression model and data also highlight SIRT1 as a potential obesity treatment for offspring of obese/overnourished dams. Recently, Nguyen et al. in another study showed that administering a SIRT1 activator, SIRT1720, every 2 days post‐weaning reduced adiposity and improved glucose tolerance in offspring of dams fed on a high‐fat diet (Nguyen et al. 2018), thus supporting the use of SIRT1 as a treatment for these offspring of high fat‐fed dams. However, these offspring were continuously treated with SIRT1720 and it is unclear whether discontinuing SIRT1720 treatment would maintain the improved metabolic state or lead to reversion to the dysregulated metabolic state as a result of maternal high‐fat feeding. The timing of treatment/intervention could perhaps dictate its long term efficacy. For example, leptin treatment during early postnatal life in ob/ob mice (leptin deficient mice) rescued hypothalamic development and prevented obesity while postnatal leptin treatment had no effect (Bouret et al. 2004). Given that SIRT1 levels are already reduced in the fetus of high fat‐fed dams (Suter et al. 2012), it is intriguing to consider whether activating SIRT1 earlier on in life could permanently correct SIRT1 expression postnatally, resulting in long term prevention of offspring obesity.

In sum, these interesting data from Nguyen et al. provide a causal role for SIRT1 in metabolic disorders in male offspring of high fat‐fed dams and illuminates SIRT1 as a promising target to prevent obesity in male offspring of obese or overnourished mothers. This study will not only prompt further research into SIRT1 treatments but also encourage the use of transgenic rodent models to interrogate the contributions of other molecular targets and the underlying mechanisms to ultimately break the intergenerational cycle of obesity.

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Competing interests

None declared.

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Sole author.

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