Giant Mice Reveal New Roles for GH in Regulating the Adipose Immune Microenvironment

The financial, social, and physical burdens of obesity have been widely studied and cited as obesity has quickly become one of the fastest growing health epidemics in America. Worldwide obesity has more than doubled since 1980. In 2014, more than a third (39%) of adults were overweight and 13% were obese, involving more than 1.9 billion adults. (http://www.who.int/mediacentre/factsheets/fs311/en/). There is growing understanding that the negative impact of the obese condition comes from the total remodeling of the microenvironment of adipose tissue, which includes adipocytes themselves and the immune cell population. In addition, we are learning that not all fat depots have the same negative impact on the body.

Historically, the existence of fat as a distinct glandular organ was actively debated at the turn of the 20th century. A review by H. Batty Shaw in 1901 discussed the various studies in which scientists were trying to understand the origin of fat cells, whether fat cells existed as distinct entities or were part of a large organ, and the fluctuations in these cells during various nutritional states (1). Adipose tissue has since been well established as a complex glandular tissue existing in distinct depots in human and animal bodies. White adipose tissue (WAT) in particular, which consists of adipocytes as well as a stromal vascular fraction (SVF), is a particularly active tissue, participating in not only metabolic regulation but also immune function and glucose regulation, to name a few [see review by Trayhurn and Beattie, 2001 (2)]. Because of the large number of factors produced by adipocytes, the influence of this organ is incredibly widespread and varied, and these primary and secondary functions are particularly well studied in disease states. In 1947, French physician Jean Vague (3) described distinct patterns of obesity and their indications for disease. He found that the masculinization of obesity (so-called android obesity of the top half of the body) was associated with a much higher incidence of diabetes and atherosclerosis, when compared with the gynoid and hypergynoid (lower trunk obesity) obese states. This association of increased abdominal fat with cardiovascular disease and metabolic syndrome has been confirmed by several groups (4–9).

The SVF is composed of preadipocytes, mesenchymal stem cells, endothelial progenitor cells, and various immune cells (macrophages, T cells, B cells, mast cells, eosinophils, and neutrophils). The makeup of the SVF changes with the nutritional status (10–14). Obesity, which increases adipokine secretion by both adipocytes and the SVF, manifests as a low-grade inflammatory state in WAT (16). The obese condition leads to recruitment of immune cells, changes in cytokine secretion, increased angiogenesis, and a shifting of macrophages from the antiinflammatory M2 state to the inflammatory M1 state (11, 15–20) [for a comparison of immune changes in WAT in lean/obese/diabetic states, see the 2015 review by Ip et al (21)]. One hormone in particular that is involved in both immune and adipose regulation is growth hormone (GH).

GH, produced and released in a pulsatile fashion by the anterior pituitary, is known to have receptors on adipocytes, preadipocytes, and the immune cells of the SVF (22–25). GH is known to be lipolytic and promotes the proliferation of preadipocytes (26, 27). GH receptor expression differs across depots, with the highest expression of human GH receptors found in epidydimal fat (28), and the expression of the human GH receptor is regulated by GH itself (29). Our laboratory has previously shown that mice lacking the leptin signal in somatotropes have decreased GH secretion, decreased somatotrope cell numbers, and increased body weight (30). Blunted in obesity, GH is known to be stimulated by leptin, and thus, the regulation of GH and the regulation of adipocytes are intertwined (31–35). Our mice lacking leptin receptors on somatotropes had higher serum adiponectin and resistin levels, indicating that the GH deficiency seen in this model was affecting the release of adipokines in the preobese state (36). Mice that are GH deficient have significantly increased fat mass beginning early in life, an accumulation that is independent of a change in energy intake (37). Young individuals with GH deficiency have large adipocytes, and adipose samples from obese GH-deficient individuals have increased proinflammatory markers (38).

In this issue of Endocrinology, Benencia et al (39) elegantly describe the immune changes that occur in the distinct depots of WAT in a state of GH excess. At the center of the study is a well-characterized mouse model of acromegaly [the bovine GH mouse (bGH)], which exhibits a major decrease in white adipose tissue in all depots. These mice also have a shortened life span, altered immune system, alterations in circulating cytokines, and (characteristic of the acromegalic state) increased and accelerated growth. The authors hypothesize that the GH signal is imperative to the maintenance and/or activation of the immune cells of WAT. Using flow cytometry, the authors isolated the various immune cells of the SVF from different fat depots. They found that the bGH mice had differences in the numbers and types of cells in the SVF across depots and compared with wild-type mice. For example, the authors found that the bGH mice had a greater number of SVF cells in subcutaneous and mesenteric fat depots relative to these depots in wild-type mice. In addition, they observed that SVF cell number and SVF cells per gram of tissue was higher in sc and mesenteric WAT depots than epididymal depots in bGF mice. Macrophages were also demonstrated to represent a higher percentage of the SVF in bGH sc and mesenteric depots relative to wild-type controls, and these macrophages more commonly exhibited an anti-inflammatory or M2 phenotype. T helper cells were also more abundant in the sc WAT of bGH mice relative to controls.

In the future, it will be interesting to determine whether these T helper cells exhibit a more proinflammatory phenotype characteristic of Th1 and Th17 cells or an anti-inflammatory phenotype characteristic of Th2 cells. The authors further demonstrated that T-regulatory cells, which are important in resolving inflammation, were elevated in the sc and mesenteric WAT depots of bGH mice relative to controls. Additionally, the use of RNA sequencing revealed a fascinating change with regard to the expression of molecules that play significant roles in immune cell biology and migration in sc fat from bGH mice, which was distinct from the expression pattern observed in epididymal fat depots. Curiously, the anti-inflammatory properties exhibited by the WAT of these mice do not contribute to longevity because these mice die young. This ground-breaking study finds that GH is able to modulate the following: 1) depot-specific changes in the proportion of SVF cells in WAT, 2) changes in the immune cell types that are recruited to the different fat depots, and 3) GH signaling in WAT that promotes an immune cell preference for the anti-inflammatory phenotype. This study will no doubt be the first in a series of investigations that will outline the differential role of GH in different fat depots.