NAD⁺-dependent deacetylase SIRT3 in adipocytes is dispensable for maintaining normal adipose tissue mitochondrial function and whole body metabolism

Abstract

Mitochondrial dysfunction in adipose tissue is involved in the pathophysiology of obesity-induced systemic metabolic complications, such as type 2 diabetes, insulin resistance, and dyslipidemia. However, the mechanisms responsible for obesity-induced adipose tissue mitochondrial dysfunction are not clear. The aim of present study was to test the hypothesis that nicotinamide adenine dinucleotide (NAD)-dependent deacetylase sirtuin-3 (SIRT3) in adipocytes plays a critical role in adipose tissue mitochondrial biology and obesity. We first measured adipose tissue SIRT3 expression in obese and lean mice. Next, adipocyte-specific mitochondrial Sirt3 knockout (AMiSKO) mice were generated and metabolically characterized. We evaluated glucose and lipid metabolism in adult mice fed either a regular-chow diet or high-fat diet (HFD) and in aged mice. We also determined the effects of Sirt3 deletion on adipose tissue metabolism and mitochondrial biology. Supporting our hypothesis, obese mice had decreased SIRT3 gene and protein expression in adipose tissue. However, despite successful knockout of SIRT3, AMiSKO mice had normal glucose and lipid metabolism and did not change metabolic responses to HFD-feeding and aging. In addition, loss of SIRT3 had no major impact on putative SIRT3 targets, key metabolic pathways, and mitochondrial function in white and brown adipose tissue. Collectively, these findings suggest that adipocyte SIRT3 is dispensable for maintaining normal adipose tissue mitochondrial function and whole body metabolism. Contrary to our hypothesis, loss of SIRT3 function in adipocytes is unlikely to contribute to the pathophysiology of obesity-induced metabolic complications.

Adipose tissue NAD + biosynthesis is required for regulating adaptive thermogenesis and whole-body energy homeostasis in mice

“…Data obtained from in vitro studies showed mitochondrial SIRT3 regulates UCP1 and PGC1α expression and oxygen consumption in brown adipocytes (31). However, whole-body Sirt3-deficient mice and adipocyte-specific mitochondrial Sirt3 knockout (AMiSKO) mice have normal BAT function and cold tolerance (32,33), suggesting SIRT3 alone is not a major downstream mediator in vivo. Nonetheless, we cannot exclude the possibility of the functional redundancy of mitochondrial sirtuins (SIRT3-5), which was recently found in retinal cells (34).…”

Monounsaturated Fatty Acids in a High‐Fat Diet and Niacin Protect from White Fat Dysfunction in the Metabolic Syndrome

“…Upon activation by increased intracellular NAD + levels, SIRT1 and SIRT3 culminate in enhancing energy expenditure and counteracting the weight gain and obesity‐related metabolic abnormalities associated with the ingestion of a lard‐based HFD in mice . Adipose SIRT1 expression improves insulin sensitivity in humans and mice, though the role of SIRT3 on mitochondrial function in adipocytes and whole‐body metabolism remains a controversy . We analyzed gene expression of SIRT1 and SIRT3 in WAT of niacin‐treated mice and found that the HFD based on milk cream was repressive for both genes while HFDs based on olive oil promoted their transcriptional activities, consistent with the selective effects of such HFDs on the levels of adipose NAD + .…”

Mitochondrial Sirtuin 3: New emerging biological function and therapeutic target

“…Obesity and diabetes are becoming ever more common around the world and are now trending with younger people. Although a recent study suggests that SIRT3 is dispensable in adipocyte metabolism and obesity-induced metabolic complications 157 , SIRT3 in fact is important in obesity and diabetes. Of note, insulin resistance and vascular dysfunction are common in obese patients, which are exacerbated by SIRT3 deficiency 158 , 159 .…”