Sex-dependent differences in skin and adipose tissue depots following high-fat diet feeding

Abstract

The prevalence of obesity in the UK is increasing, with a significant proportion of the worldwide population currently overweight. Pre-menopausal women are at a lower risk of obesity-associated metabolic diseases, such as Type 2 diabetes mellitus despite having more body fat than men of a similar age. However, the sex-dependent associations between adiposity and metabolic diseases and whether these occur at early stages of disease development, remain unclear. The sex-dependent differences in white adipose tissue (WAT) distribution, function and metaflammation could contribute to the sex dimorphism in the development of obesity-associated metabolic diseases. The impact of obesity on the skin and its dermal WAT (dWAT) depot have had limited exploration, despite the known clinical manifestations on the skin of obese individuals. In addition, IKBKE is a protein that is overexpressed in WAT during obesity and is involved in regulating metaflammation, although its sex-dependent actions remain unknown. This thesis aimed to explore in pre-clinical murine models whether a) there are any anatomical- and/or sex-specific differences in the size of WAT depots relative to body weight (BW) and whether these are associated with hyperglycaemia or increase in relative liver mass/fat, b) the dWAT depot and skin morphology are altered in a sex-dependent manner following high-fat diet (HFD) feeding and c) the response to HFD feeding is sex-dependent in mice lacking Ikbke. This thesis also aimed to d) validate the generation of a myeloid-specific Ikbke knockout murine model. During the early stages of disease development, the linear relationship between BW and the mass of visceral depots was lost only in male mice with HFD-induced hyperglycaemia. By contrast, the linear relationship with the Inguinal WAT depot was retained in all mice irrespective of sex, diet, or glycaemic status. Increased relative liver mass was only observed in HFD-fed male mice, although the presence of liver vacuoles was similar in both sexes. An increase in dWAT thickness and dWAT adipocyte hypertrophy was observed in overweight male but not female mice. Furthermore, the absence of a functional IKBKE protein resulted in increased adiposity in obese female, but not male mice, when compared to wildtype littermates. Finally, the absence of functional IKBKE protein was confirmed in a myeloid-specific Ikbke knockout murine model. Collectively these findings revealed depot-related differences in the development of obesity-associated metabolic diseases that occur during the early development of hyperglycaemia. From the early stages of disease progression, there is a dysregulated relationship between BW and visceral depots, increased liver mass and skin changes that were more pronounced in male compared to female mice. Lastly, the inflammatory protein, IKBKE may be required for the regulation of HFD-induced adiposity in a sex-dependent manner.

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Identifiers

ORCID for Maria Kousetti: orcid.org/0000-0002-0695-5313

ORCID for Jaswinder Sethi: orcid.org/0000-0003-4157-0475

ORCID for Pete Worsley: orcid.org/0000-0003-0145-5042

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