Mild Suppression of Hyperinsulinemia to Treat Obesity and Insulin Resistance

Highlights

Insulin acts on multiple tissues to stimulate the synthesis and storage of carbohydrates, lipids, and proteins.

Hypersecretion of insulin is a physiological contributor to diet-induced obesity in animal models.

Obesity can be treated in adult mice following an acute reduction in insulin secretion.

The results of clinical studies are mixed, and additional, more specific manipulations are needed to translate the preclinical knowledge for humans.

Insulin plays roles in lipid uptake, lipolysis, and lipogenesis, in addition to controlling blood glucose levels. Excessive circulating insulin is associated with adipose tissue expansion and obesity, yet a causal role for hyperinsulinemia in the development of mammalian obesity has proven controversial, with many researchers suggesting it as a consequence of insulin resistance. Recently, evidence that specifically reducing hyperinsulinemia can prevent and reverse obesity in animal models has been presented. Our experiments, and others in this field, question the current dogma that hyperinsulinemia is a response to obesity and/or insulin resistance. In this review, we discuss preclinical evidence in the context of the broader literature and speculate on the possibility of clinical translation of alternative approaches for treating obesity.

Introduction

Insulin is a powerful anabolic hormone secreted from pancreatic β-cells that acts on multiple tissues to stimulate the synthesis and storage of carbohydrates, lipids, and proteins. A lack of appropriate insulin production and secretion, and/or the inability of tissues to adequately respond to insulin, contribute to impaired glucose homeostasis and the pathogenesis of type 2 diabetes [1]. Inappropriate insulin secretion and insulin resistance are also associated with other disorders, such as obesity, atherosclerosis, and hypertension 1, 2, 3, 4. The effects of insulin on glucose homeostasis have been well studied at both the cell biological and whole body physiological levels, but insulin’s more potent effects on lipid homeostasis have been studied less in vivo. Clinical correlations between hyperinsulinemia (see Glossary) and dyslipidemia were already well known 4, 5, yet it was only in 2012 when we published on the specific in vivo effects of reduced insulin production in the context of obesity prevention that the causal relationship was formally addressed [6]. We have since expanded on these observations to include the analysis of insulin sensitivity in aged animals, as well as lifespan 7, 8. Most recently, we have found that existing obesity can be reversed with a specific, partial reduction of insulin production [9]. In this review, we will start by reviewing the molecular mechanisms mediating insulin action in adipose tissue, as well as insulin production and secretion, with a discussion of how these processes are imbalanced in obesity and early type 2 diabetes. We will then focus on what we have learned about obesity and insulin sensitivity by specifically and directly modulating insulin production in a variety of contexts. We will place our results in the scope of the recent broader literature and pose questions about future research and clinical opportunities for treating obesity and insulin resistance by mild suppression of insulin. We hope to address how the early normalization of insulin production and secretion can play a role in the prevention and reversal of obesity, insulin resistance, and type 2 diabetes.

Adipose tissue remodeling can theoretically occur via lipid hypertrophy and/or hyperplasia 10, 11, and there is evidence that insulin has multiple direct effects on both cellular lipid metabolism [12] and adipocyte differentiation [13]. Insulin acts to inhibit lipolysis in adipocytes in the postprandial state [14], while promoting lipid storage through stimulating the uptake, synthesis, and storage of triglycerides in adipocytes [15]. Early experiments in rodents reveal that insulin injections into fat pads leads directly to tissue expansion due to lipid accumulation [5]. Mice with specific loss of insulin receptors in white adipose tissue have impaired adipose tissue development and are protected against diet-induced obesity, supporting the role of insulin action in adipose expansion 16, 17, 18. Adipogenesis can be stimulated with insulin action by two mechanisms: (i) through activation of C/EBP-β and C/EBP-α transcription factors, which induce the transcription of peroxisome proliferator-activated receptor γ (PPARγ) an important regulator of adipose tissue formation, and (ii) through inhibiting FOXO1 activity, which under normal conditions negatively regulates adipogenesis [19]. Mice that lack PPARγ in adipose tissue have lean bodies and lower fasting insulin levels compared with control littermates, but this was only noted when the mice were challenged with a high-fat diet. However, due to impaired function of adipose tissue, these mice have increased lipid accumulation within their liver and muscle tissue [20]. S6 kinase 1 (S6K1) is activated by nutrients and/or insulin, leading to an increased phosphorylation of insulin receptor substrate 1 (IRS1). Mice with whole body S6K1 knockout have reduced levels of IRS1 phosphorylation and dampened insulin signaling. S6K1 knockout mice, on both chow and high-fat diets, have lower body masses due to significantly smaller adipocytes and increased lipolysis compared with control mice [21]; however generalized development of these mice appears impaired as they have leaner body masses prior to the onset of the diets 21, 22. Interestingly, loss of insulin receptors also prevents development of brown adipose tissue in mice [23]. Together, the above findings offer evidence that insulin action impacts several adipose tissue depots.

White adipose tissue can be separated into subtypes based on function, distribution, and contribution to obesity. Subcutaneous and visceral adipose tissue differ in several regards, including adipocyte type, function, lipolytic activity, vascularity, and innervation, as well as their response to insulin and other hormones [24]. Subcutaneous adipose tissue is the natural reservoir for excess energy, however when this storage area becomes overwhelmed or its ability to generate new adipocytes is impaired, lipids will accumulate in other locations, including visceral depots and organs such as the liver and pancreas. Visceral adipose tissue has been reported to be more metabolically active with enhanced sensitivity to lipolysis and appears to be more responsive to weight loss [24]. In a rodent model of type 2 diabetes, insulin treatment resulted in preferential expansion of subcutaneous adipose tissue compared with visceral tissue [25]. The mechanisms that determine fat pad expansion in humans are incompletely understood and may depend on sex, ethnicity, and age [26].