Autophagy regulates adipose mass and differentiation in mice

Abstract

The relative balance between the quantity of white and brown adipose tissue can profoundly affect lipid storage and whole-body energy homeostasis. However, the mechanisms regulating the formation, expansion, and interconversion of these 2 distinct types of fat remain unknown. Recently, the lysosomal degradative pathway of macroautophagy has been identified as a regulator of cellular differentiation, suggesting that autophagy may modulate this process in adipocytes. The function of autophagy in adipose differentiation was therefore examined in the current study by genetic inhibition of the critical macroautophagy gene autophagy-related 7 (Atg7). Knockdown of Atg7 in 3T3-L1 preadipocytes inhibited lipid accumulation and decreased protein levels of adipocyte differentiation factors. Knockdown of Atg5 or pharmacological inhibition of autophagy or lysosome function also had similar effects. An adipocyte-specific mouse knockout of Atg7 generated lean mice with decreased white adipose mass and enhanced insulin sensitivity. White adipose tissue in knockout mice had increased features of brown adipocytes, which, along with an increase in normal brown adipose tissue, led to an elevated rate of fatty acid, β-oxidation, and a lean body mass. Autophagy therefore functions to regulate body lipid accumulation by controlling adipocyte differentiation and determining the balance between white and brown fat. IntroductionObesity is characterized by an expansion of adipose tissue mass resulting from increased adipocyte number and/or size. Lipids in the form of triglycerides (TG) accumulate in various anatomical locations that differ in several regards including whether they are composed primarily of white or brown adipocytes. These 2 distinct types of adipocytes differ in their lipid content and metabolic functions. White adipose tissue (WAT) serves the primary function of lipid storage in the fed state and with fasting releases fatty acids from the breakdown of TG into the circulation for muscle energy production. In contrast, brown adipose tissue (BAT) has more limited TG storage and does not secrete fatty acids but instead uses them for autonomous energy expenditure and heat generation (1). Although the amount of BAT in adult humans has been previously considered to be minimal, recent findings of significant concentrations of brown adipocytes in adult humans (2-5) have raised the possibility that the balance between WAT and BAT mass may be one factor that regulates the development of obesity and its severity (6). Manipulating the process of adipocyte differentiation in order to promote more BAT in place of WAT may therefore be a novel approach to the treatment of obesity and its associated problems (7).Factors determining the differential development of WAT versus BAT remain poorly defined. In mammals, WAT and BAT generally develop before birth, although in rodents, WAT develops postnatally (8). Recent studies suggest that these fat cell populations are not static and may in fact continue to undergo significant cell turnover (9)...

Autophagy at the crossroads of catabolism and anabolism

“…Similarly, autophagy inhibition in 3T3-L1 pre-adipocytes resulted in reduced levels of markers of white adipocyte differentiation and transcription factors that promote such differentiation along with decreased triglycerides 81 . In vivo studies using adipocyte-specific Atg7-deficient mice also showed that autophagy supports WAT differentiation 82,83 . Specifically, this deletion resulted in lean mice regardless of whether they had been fed a regular or high-fat diet.…”

Autophagy deficiency in myeloid cells increases susceptibility to obesity-induced diabetes and experimental colitis

“…11,12 As these results suggest that autophagy deficiency is a proinflammatory condition particularly in relation to inflammasome activation, deficient autophagy can be a factor in the development of T2D associated with low-grade inflammation and inflammasome activation. Although the role of autophagy of diverse tissues in body metabolism has been intensively investigated, [13][14][15][16][17][18][19][20][21] the importance of autophagy of myeloid cells such as Mfs (macrophages) in the regulation of systemic insulin sensitivity and in the development of T2D has not been clearly elucidated. Besides metabolic syndrome, IBD (inflammatory bowel disease) is a prototypic disease associated with autophagy deficiency inducing aggravated tissue inflammation.…”

A novel Atg5-shRNA mouse model enables temporal control of Autophagy in vivo

“…Similar to the systemic atg7 KO mice, ATG5i mice on dox appeared smaller in size with smaller weight gain in both genders (Figure 1(c)). Anatomical inspection revealed, as in the whole-body somatic atg7 KO mice and/or atg5 and atg7 KO mice, a reduction of fat [16] and muscle tissues (Figures 1(d,e)) [17], with the presence of hepatomegaly [9], splenomegaly, and seminal vesicle atrophy (Figure 1(fh)) [18]. …”