1. Introduction

The global obesity epidemic has developed over the last half century [1]. Obesity underlies many 21st century chronic diseases and confers a substantial socio-economic burden globally, including contributing towards a large proportion of overall healthcare costs [1]. Obesity affects people of any age, class, ethnicity or socio-economic group, with a current prevalence in the UK of one in four adults [1].

Weight gain and obesity mediates most of its direct medical sequelae through worsening insulin sensitivity and, as such, the development of insulin resistance (IR) ^[2]. In addition to malignancies such as endometrial carcinoma ^[1][3], IR underlies the cardio-metabolic dysfunction that associates with obesity. This includes type 2 diabetes mellitus (T2D) ^[1], polycystic ovary syndrome (PCOS) ^[4][5] and hypertension ^[6]. Furthermore, such obesity-related IR is compounded by the development of other obesity-related conditions such as obstructive sleep apnoea (OSA) ^[7] and male obesity-associated secondary hypogonadism (MOSH) ^[8]. As such, IR lies at a key junction that is itself influenced by multiple and complex pathways but also instigates multiple and complex downstream effects that ultimately manifest with metabolic and cognitive dysfunction.

Weight gain and obesity mediates most of its direct medical sequelae through worsening insulin sensitivity and, as such, the development of insulin resistance (IR) [2]. In addition to malignancies such as endometrial carcinoma [1,3], IR underlies the cardio-metabolic dysfunction that associates with obesity. This includes type 2 diabetes mellitus (T2D) [1], polycystic ovary syndrome (PCOS) [4,5] and hypertension [6]. Furthermore, such obesity-related IR is compounded by the development of other obesity-related conditions such as obstructive sleep apnoea (OSA) [7] and male obesity-associated secondary hypogonadism (MOSH) [8]. As such, IR lies at a key junction that is itself influenced by multiple and complex pathways but also instigates multiple and complex downstream effects that ultimately manifest with metabolic and cognitive dysfunction.

In this concise review (summarised in

Figure 1), we explore the role of weight gain with excess adiposity and obesity in the development of IR and the effects of IR on the subsequent development of both metabolic and cognitive dysfunction. We also consider the reversibility of IR through the effective implementation of lifestyle improvement strategies including optimisation of physical activity, diet and sleep. Although inherent challenges limit the successful longer-term maintenance of body weight following initial weight loss ^[9][10]], successful adoption of a healthy lifestyle regarding these key lifestyle factors (regardless of the magnitude of weight loss) provides a sensible and feasible means of improving insulin sensitivity and the overall health and wellbeing of the populace.

), we explore the role of weight gain with excess adiposity and obesity in the development of IR and the effects of IR on the subsequent development of both metabolic and cognitive dysfunction. We also consider the reversibility of IR through the effective implementation of lifestyle improvement strategies including optimisation of physical activity, diet and sleep. Although inherent challenges limit the successful longer-term maintenance of body weight following initial weight loss [9,10], successful adoption of a healthy lifestyle regarding these key lifestyle factors (regardless of the magnitude of weight loss) provides a sensible and feasible means of improving insulin sensitivity and the overall health and wellbeing of the populace.

Figure 1.

2. Role of Obesity in the Development of IR

The clinical definition of IR is the inability of a known quantity of insulin (either endogenous or exogenous) to increase the uptake and utilisation of glucose in an individual by the same degree as that in a normal population ^[11]. Insulin binds to its plasma membrane receptor and mediates its cellular effects through a series of protein–protein interactions ^[11]. There are two main postreceptor cellular pathways implicated: (i) the phosphatidylinositol 3-kinase (PI3-K) pathway and (ii) the mitogen-activated protein kinase (MAP-K) pathway ^[12][13]. Each of these pathways confers different cellular functions of insulin. The PI3-K pathway regulates cellular intermediary metabolism, whereas the MAP-K pathway controls growth processes and mitoses ^[11]. Importantly, obesity-related IR appears to affect predominantly and commensurately the PI3-K pathway, with the MAP-K pathway remaining relatively unaffected ^{[11][12][13][14]}. Therefore, a more descriptive definition of IR is perhaps “metabolic insulin resistance” ^[14]. The relative sparing of the MAP-K insulin pathway in obesity-related IR may help to explain the known association between obesity and malignancy and promotes IR and the harmful effects of compensatory hyperinsulinaemia as central to the pathogenesis of such tumours ^[15].

The clinical definition of IR is the inability of a known quantity of insulin (either endogenous or exogenous) to increase the uptake and utilisation of glucose in an individual by the same degree as that in a normal population [11]. Insulin binds to its plasma membrane receptor and mediates its cellular effects through a series of protein–protein interactions [11]. There are two main postreceptor cellular pathways implicated: (i) the phosphatidylinositol 3-kinase (PI3-K) pathway and (ii) the mitogen-activated protein kinase (MAP-K) pathway [12,13]. Each of these pathways confers different cellular functions of insulin. The PI3-K pathway regulates cellular intermediary metabolism, whereas the MAP-K pathway controls growth processes and mitoses [11]. Importantly, obesity-related IR appears to affect predominantly and commensurately the PI3-K pathway, with the MAP-K pathway remaining relatively unaffected [11,12,13,14]. Therefore, a more descriptive definition of IR is perhaps “metabolic insulin resistance” [14]. The relative sparing of the MAP-K insulin pathway in obesity-related IR may help to explain the known association between obesity and malignancy and promotes IR and the harmful effects of compensatory hyperinsulinaemia as central to the pathogenesis of such tumours [15].

Given the close link between obesity and the development of PI3-K dysfunctional IR, it is important to explore how obesity mediates its effects on the insulin pathway. It seems likely that multiple and complex pathways are implicated, with inter-linking and multidirectional effects. It is beyond the scope of this concise review to provide a detailed exposition of the complexities of molecular mechanisms. Rather, we provide an overview of the current main theories that link obesity with IR.

Chronic inflammation: The close association between body weight and IR ^[12][16] is likely mediated, at least in part, through inflammatory pathways ^[17]. Weight gain and obesity causes changes in the release of key adipokines and cytokines from adipose tissue that in turn manifest in both paracrine and endocrine effects, with the latter from release into the plasma. These changes include increased release of leptin and plasminogen activator inhibitor-1 and reduced release of adiponectin ^[18]. These key changes result in a generalised low-grade inflammatory response, mediated through infiltration of macrophages and other immune cells into metabolic organs, such as white adipose tissue (WAT), skeletal muscle, liver and pancreas ^[19]. This process associates with a shift from a predominantly anti-inflammatory to a proinflammatory profile ^[20]. Macrophage release of proinflammatory cytokines (including interleukin-1β that activates the “NOD-, LRR- and pyrin domain-containing protein 3” (NLRP3) inflammasome) result in autocrine and paracrine effects that enhance IR ^[20]. This chronic low-grade inflammatory response also facilitates tumour cell motility and invasion ^[18].

The close association between body weight and IR [12,16] is likely mediated, at least in part, through inflammatory pathways [17]. Weight gain and obesity causes changes in the release of key adipokines and cytokines from adipose tissue that in turn manifest in both paracrine and endocrine effects, with the latter from release into the plasma. These changes include increased release of leptin and plasminogen activator inhibitor-1 and reduced release of adiponectin [18]. These key changes result in a generalised low-grade inflammatory response, mediated through infiltration of macrophages and other immune cells into metabolic organs, such as white adipose tissue (WAT), skeletal muscle, liver and pancreas [19]. This process associates with a shift from a predominantly anti-inflammatory to a proinflammatory profile [20]. Macrophage release of proinflammatory cytokines (including interleukin-1β that activates the “NOD-, LRR- and pyrin domain-containing protein 3” (NLRP3) inflammasome) result in autocrine and paracrine effects that enhance IR [20]. This chronic low-grade inflammatory response also facilitates tumour cell motility and invasion [18].

Mitochondrial dysfunction:

Obesity can overwhelm the capacity of eutopic WAT depots. In this scenario, lipid deposition occurs ectopically in nonadipose tissues, such as skeletal muscle and liver. In recent years, a great deal of evidence supports an important role of mitochondrial dysfunction in the development of obesity-related IR, stimulated through ectopic fat deposition [21]. Lipid-induced production of reactive oxygen species (ROS) within skeletal muscle promotes mitochondrial dysfunction and the development of IR [21]. Furthermore, a harmful feedback loop can occur whereby ROS production from impaired mitochondria results in further mitochondrial dysfunction and the worsening of IR [21]. Related to the mitochondrial dysfunction and production of ROS, obesity-induced endoplasmic reticulum (ER) stress and inflammation within the liver may also result in hepatic IR and gluconeogenesis [22].

Gut microbiota dysbiosis:

In recent years, there has been a transformation in our understanding of the gut microbiota and its role in health and chronic disease. A number of our data originate from rodent models. In a recent meta-analysis of data on changes in the gut microbiota in high-fat diet (HFD)-induced obese rodents, there was a demonstration of the structural and functional dysbiosis of the gut microbiota in HFD-induced obesity [23]. Compared with their lean counterparts, HFD-induced obese rodents increased Lactococcus and reduced Turicibacter, each consistent with an enhanced inflammatory response [23]. There was also an abundance of Dorea, Oscillospira and Ruminococcus. Furthermore, functional differences in the gut microbiota between lean and HFD-induced obese rodents occurred, with the latter manifesting metabolic pathways that converge on the biosynthesis of lipid and carbohydrate and short chain fatty acid (SCFA) metabolism [23]. From these data, it is not possible to implicate clearly gut microbiota dysbiosis as a mediator between obesity and IR. The gut microbiota has multiple and complex effects on appetite and metabolism and may influence body weight. Furthermore, we should be cautious about extrapolating data from rodent studies into humans. However, the rodent data outlined here provide compelling evidence that HFD-induced obesity associates with both structural and functional gut microbiota dysbiosis, consistent with the promotion of a proinflammatory state and the subsequent development of IR.

Adipose extracellular matrix (ECM) remodelling:

In response to nutritional cues, adipocytes and their precursors need to change their shape, size and function. This process requires remodelling within a WAT ECM [24]. Weight gain, with its associated expansion of WAT depots, results in a localised hypoxic response: the expanded WAT essentially outstrips its own vascular supply and becomes hypoxic, resulting in the acceleration of fibrosis and inflammation within the expanding WAT [24]. In this scenario, the excessive deposition of ECM within WAT limits the angiogenic response. Given the regulation of insulin sensitivity by ECM receptors, such as CD44 and integrins, the accumulation of ECM within the WAT results in the worsening of IR [24].

In addition to the mechanisms outlined above, numerous other factors influence insulin sensitivity, some of which may be influenced in some way indirectly by weight gain (excess adiposity) and obesity. Amongst these factors include genetic abnormalities that affect the insulin receptor or the proteins of the cellular insulin pathway and fetal malnutrition [11]. Vitamin D may also influence IR and has received a great deal of attention in recent years. In one study on more than 2200 Greek schoolchildren aged between 9 and 13 years, the prevalence of the vitamin D insufficiency was significantly greater in children with obesity compared with in their overweight and normal weight counterparts (60.5% vs. 51.6%) [25]. Furthermore, children with IR had a 1.48-fold greater likelihood of vitamin D insufficiency compared with those without IR [25]. This study, as with much of the literature on the influence of vitamin D on IR, reported on the association data in which the proof of causality is lacking. Future studies should explore potential causal mechanisms linking vitamin D insufficiency with IR, and the degree to which obesity mediates the development of IR through effects on vitamin D. Possible indirect mechanisms include reduced sunlight exposure of the skin or increased sequestration of vitamin D within WAT with consequent reduced levels in the plasma.

Obesity-related IR appears confined to the PI3-K postreceptor insulin pathway that regulates the cellular metabolic effects of insulin. Obesity contributes towards the development of IR through numerous and complex mechanisms, which implicate changes in adipokines, cytokines, inflammatory response, mitochondrial dysfunction, ROS production, ER stress, gut microbial dysbiosis and remodelling of adipose ECMs. From this perspective, IR is located at a crossroad or gateway that functions as a key expedient linking weight gain and obesity with its metabolic and cognitive sequelae.