Recent studies suggest that, even within a single adipose depot, there may be distinct subpopulations of adipocytes. To investigate this cellular heterogeneity, we have developed multiple conditionally immortalized clonal preadipocyte lines from white adipose tissue of mice. Analysis of these clones reveals at least three white adipocyte subpopulations. These subpopulations have differences in metabolism and differentially respond to inflammatory cytokines, insulin, and growth hormones. These also have distinct gene expression profiles and can be tracked by differential expression of three marker genes: Wilms’ tumor 1, transgelin, and myxovirus 1. Lineage tracing analysis with dual‐fluorescent reporter mice indicates that these adipocyte subpopulations have differences in gene expression and metabolism that mirror those observed in the clonal cell lines. Furthermore, preadipocytes and adipocytes from these subpopulations differ in their abundance in different fat depots. Thus, white adipose tissue, even in a single depot, is comprised of distinct subpopulations of white adipocytes with different physiological phenotypes. These differences in adipocyte composition may contribute to the differences in metabolic behavior and physiology of different fat depots.

Adipose tissue not only stores energy, but also controls metabolism through secretion of hormones, cytokines, proteins, and microRNAs that affect the function of cells and tissues throughout the body. Adipose tissue is organized into discrete depots throughout the body, and these depots are differentially associated with insulin resistance and increased risk of metabolic disease. In addition to energy-dissipating brown and beige adipocytes, recent lineage tracing studies have demonstrated that individual adipose depots are composed of white adipocytes that are derived from distinct precursor populations, giving rise to distinct subpopulations of energy-storing white adipocytes. In this review, we discuss this developmental and functional heterogeneity of white adipocytes both between and within adipose depots. In particular, we will highlight findings from our recent manuscript in which we find and characterize three major subtypes of white adipocytes. We will discuss these data relating to the differences between subcutaneous and visceral white adipose tissue and in relationship to previous work deciphering adipocyte heterogeneity within adipose tissue depots. Finally, we will discuss the possible implications of adipocyte heterogeneity may have for the understanding of lipodystrophies.

Growth hormone (GH) has long been known to stimulate lipolysis and insulin resistance; however, the molecular mechanisms underlying these effects are unknown. In the present study, we demonstrate that GH acutely induces lipolysis in cultured adipocytes. This effect is secondary to the reduced expression of a negative regulator of lipolysis, Fat Specific Protein 27 (FSP27) at both the mRNA and protein level. These effects are mimicked in vivo as transgenic over-expression of GH leads to a reduction of FSP27 expression. Mechanistically, we show GH modulation of FSP27 expression is mediated through activation of both MEK/ERK and STAT5 dependent intracellular signaling. These two molecular pathways interact to differentially manipulate peroxisome proliferator-activated receptor gamma activity (PPARγ) on the FSP27 promoter. Furthermore, over-expression of FSP27 is sufficient to fully suppress GH-induced lipolysis and insulin resistance in cultured adipocytes. Taken together, these data decipher a molecular mechanism by which GH acutely regulates lipolysis and insulin resistance in adipocytes.

The increasing prevalence of obesity is a major factor driving the worldwide epidemic of type 2 diabetes and metabolic syndrome. Adipose tissue not only stores energy, but also controls metabolism through secretion of hormones, cytokines, proteins, and microRNAs that affect the function of cells and tissues throughout the body. Accumulation of visceral white adipose tissue (WAT) leads to central obesity and is associated with insulin resistance and increased risk of metabolic disease, whereas accumulation of subcutaneous WAT leads to peripheral obesity and may be protective of metabolic syndrome. While much attention has been paid to identifying differences between white, brown and brite/ beige adipocytes, there is growing evidence that there is functional heterogeneity among white adipocytes themselves. This heterogeneity, includes depot-specific differences in development, inflammation, and endocrine properties. In addition to the depot-specific differences, even within a single fat depot, WAT is composed of developmentally and phenotypically distinct subpopulations of adipocytes. The following chapter will introduce this concept of white adipocyte heterogeneity.

Recent studies have shown that heterogeneity among adipocytes exists even within a single white adipose tissue (WAT) depot. Our lab has uncovered developmentally distinct subpopulations of WAT adipocytes that are distinguished by the expression of these genes: Wilms’ Tumor 1 (Wt1) (Type 1), Transgelin (Tagln) (Type 2), and Myxovirus 1 (Mx1) (Type 3). Utilizing Cre transgenic mice, transcription of which is directed by the promoters of these marker genes, lineage tracing analysis showed that these three preadipocyte subpopulations independently gave rise to adipocytes in vivo , and differentially contribute to the adipose tissue depots. In high-fat diet induced obesity, Type 1 and Type 2 adipocytes are found roughly the same abundance in perigonadal adipose tissue, with only low numbers of Type 3 adipocytes observed. Macrophages, organized into crown like structures (CLS) around dead and dying adipocytes, are detected in the vicinity of Type 1 adipocytes derived from Wt1 positive lineage. The distributions of Type 1 adipocytes and of CLS were determined by Kernel density estimation, and found to be significantly overlapped. On the other hand, over 80% of CLS are found in direct contact with Type 2 adipocytes in the perigonadal adipose tissue. This finding indicates that diet-induced obesity preferentially causes increased death of Type 2 adipocytes compared to other adipocyte subtypes. Taken together, these data indicate that adipocyte subpopulations, at least in part, mediate the inflammatory response in adipose tissue.