Adipose Tissue Inflammation Is Directly Linked to Obesity-Induced Insulin Resistance, while Gut Dysbiosis and Mitochondrial Dysfunction Are Not Required

Abstract

Obesity is associated with adipose tissue hypertrophy, systemic inflammation, mitochondrial dysfunction, and intestinal dysbiosis. Rodent models of high fat diet (HFD)-feeding or genetic deletion of multi-functional proteins involved in immunity and metabolism are often used to probe the aetiology of obesity; however, these models make it difficult to divorce the effects of obesity, diet composition, or immunity on endocrine regulation of blood glucose. We therefore investigated the importance of adipose inflammation, mitochondrial dysfunction, and gut dysbiosis for obesity-induced insulin resistance using a spontaneously obese mouse model. We examined metabolic changes in skeletal muscle, adipose tissue, liver, the intestinal microbiome, and whole-body glucose control in spontaneously hyperphagic C57Bl/6J mice compared to lean littermates. A separate subset of lean and obese mice were subject to 8 weeks of obesogenic HFD-feeding, or to pair feeding of a standard rodent diet. Hyperphagia, obesity, adipose inflammation, and insulin resistance were present in obese mice despite consuming a standard rodent diet, and these effects were blunted with caloric restriction. However, hyperphagic obese mice had normal mitochondrial respiratory function in all tissues tested and no discernable intestinal dysbiosis relative to lean littermates. In contrast, feeding mice an obesogenic HFD altered the composition of the gut microbiome, impaired skeletal muscle mitochondrial bioenergetics, and promoted poor glucose control. These data show that adipose inflammation occurred in all models of obesity, but gut dysbiosis and mitochondrial dysfunction are not always required for obesity-induced insulin resistance. Rather, changes in the intestinal microbiome and mitochondrial bioenergetics may reflect physiological consequences of HFD-feeding.

Hyperinsulinemia in Obesity, Inflammation, and Cancer

“…Inflammation is associated with metabolic dysfunction such as obesity and insulin resistance [133]. Several studies suggest that obesity-associated, chronic, low-grade inflammation can cause insulin resistance in metabolic tissues like liver, muscle, and adipose tissues [134][135][136].…”

Mechanisms of muscle insulin resistance and the cross‐talk with liver and adipose tissue

“…Although evidence suggests a link between mitochondrial dysfunction and insulin resistance, dysfunctional mitochondria may not be necessary to induce insulin resistance in adipocytes. Recently, a study investigating the role of adipose inflammation, mitochondrial dysfunction, and gut dysbiosis in obesity‐induced insulin resistance, the authors found that mitochondrial dysfunction and gut dysbiosis occurred during HFD‐feeding but was not present in spontaneously obese mice (Petrick et al., 2020). This suggests that mitochondrial dysfunction may be diet‐related and is not always required for obesity‐induced insulin resistance.…”

“…Many mechanistic studies examining the relationship between obesity and its associated chronic low‐grade inflammation have highlighted the role of pattern recognition receptors (PPRs), specifically Toll‐like receptors (TLRs) and Nucleotide‐binding oligomerization domain (NOD)‐like receptors or (NLRs), and their impact on insulin resistance (Petrick et al., 2020; Schertzer et al., 2011). Obesity is thought to provoke increased intestinal permeability, giving rise to higher circulating levels of lipopolysaccharide (LPS) emitted by intestinal gram‐negative bacterial species (Saad et al., 2016).…”

Diammonium Glycyrrhizinate Ameliorates Obesity Through Modulation of Gut Microbiota-Conjugated BAs-FXR Signaling

“…Obesity, mainly caused by genetic and environmental factors, is a worldwide epidemic metabolic disease characterized by excessive fat accumulation. It not only affects body appearance but also contributes to many chronic inflammatory diseases, such as type 2 diabetes, hepatic steatosis and cardiovascular diseases (Petrick et al, 2020;Scheithauer et al, 2020;Agüera et al, 2021). However, the global prevalence of obesity is immensely high and alarming projections suggest that more than one billion people will be obese by 2030 (Kelly et al, 2008;Finucane et al, 2011).…”