Molecular and Neuroendocrine Determinants of Seasonal Body Weight Regulation

This thesis deals with the characterisation of neuroendocrine pathways involved in seasonal body regulation revealed by the Siberian hamster (Phodopus sungorus). In the neuronal centre of body weight regulation, the hypothalamus, central signal transduction of the "adiposity signals" leptin and insulin (both inhibit food intake) and of the food intake stimulating hormone ghrelin was investigated comprehensively. Another aim of this thesis was the identification of the molecular identity underlying the phenomenon of leptin resistance, a key event in the onset of obesity. Furthermore, possible convergence of central leptin- and insulin signalling pathways was investigated. The hypothalamic signal transduction of both hormones was strikingly seasonally regulated implying a central role of these humoral signals in mediating seasonal body weight changes. The molecular identity of seasonally induced leptin resistance could be unravelled: It is caused by modulation of the signal transduction cascade distal to the leptin receptor. Moreover, the results of this thesis contradict to the popular opinion of possible synergistic effects conveyed by the anorexigenic hormones leptin and insulin which are related to their hypothalamic signalling. Ghrelin and its central signalling by the ghrelin receptor is very likely responsible for the acute regulation of food intake whereas it does not act on chronic changes in energy homeostasis (seasonal body weight cycles)

Photoperiodic and diurnal regulation of WNT signalling in the arcuate nucleus of the 1 female Djungarian hamster, Phodopus sungorus

yesThe WNT pathway was shown to play an important role in the adult central nervous system. We previously identified the WNT pathway as a novel integration site of the adipokine leptin in mediating its neuroendocrine control of metabolism in obese mice. Here we investigated the implication of WNT signaling in seasonal body weight regulation exhibited by the Djungarian hamster (Phodopus sungorus), a seasonal mammal that exhibits profound annual changes in leptin sensitivity. We furthermore investigated whether crucial components of the WNT pathway are regulated in a diurnal manner. Gene expression of key components of the WNT pathway in the hypothalamus of hamsters acclimated to either long day (LD) or short day (SD) photoperiod was analyzed by in situ hybridization. We detected elevated expression of the genes WNT-4, Axin-2, Cyclin-D1, and SFRP-2, in the hypothalamic arcuate nucleus, a key energy balance integration site, during LD compared with SD as well as a diurnal regulation of Axin-2, Cyclin-D1, and DKK-3. Investigating the effect of photoperiod as well as leptin on the activation (phosphorylation) of the WNT coreceptor LRP-6-(Ser1490) by immunohistochemistry, we found elevated activity in the arcuate nucleus during LD relative to SD as well as after leptin treatment (2 mg/kg body weight). These findings indicate that differential WNT signaling may be associated with seasonal body weight regulation and is partially regulated in a diurnal manner in the adult brain. Furthermore, they suggest that this pathway plays a key role in the neuroendocrine regulation of body weight and integration of the leptin signal

Proteomics reveals that a high-fat diet induces rapid changes in hypothalamic proteins related to neuronal damage and inflammation

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Photoperiodic and diurnal regulation of WNT signalling in the arcuate nucleus of the 1 female Djungarian hamster, Phodopus sungorus

yesThe WNT pathway was shown to play an important role in the adult central nervous system. We previously identified the WNT pathway as a novel integration site of the adipokine leptin in mediating its neuroendocrine control of metabolism in obese mice. Here we investigated the implication of WNT signaling in seasonal body weight regulation exhibited by the Djungarian hamster (Phodopus sungorus), a seasonal mammal that exhibits profound annual changes in leptin sensitivity. We furthermore investigated whether crucial components of the WNT pathway are regulated in a diurnal manner. Gene expression of key components of the WNT pathway in the hypothalamus of hamsters acclimated to either long day (LD) or short day (SD) photoperiod was analyzed by in situ hybridization. We detected elevated expression of the genes WNT-4, Axin-2, Cyclin-D1, and SFRP-2, in the hypothalamic arcuate nucleus, a key energy balance integration site, during LD compared with SD as well as a diurnal regulation of Axin-2, Cyclin-D1, and DKK-3. Investigating the effect of photoperiod as well as leptin on the activation (phosphorylation) of the WNT coreceptor LRP-6-(Ser1490) by immunohistochemistry, we found elevated activity in the arcuate nucleus during LD relative to SD as well as after leptin treatment (2 mg/kg body weight). These findings indicate that differential WNT signaling may be associated with seasonal body weight regulation and is partially regulated in a diurnal manner in the adult brain. Furthermore, they suggest that this pathway plays a key role in the neuroendocrine regulation of body weight and integration of the leptin signal

Molecular and Neuroendocrine Determinants of Seasonal Body Weight Regulation

This thesis deals with the characterisation of neuroendocrine pathways involved in seasonal body regulation revealed by the Siberian hamster (Phodopus sungorus). In the neuronal centre of body weight regulation, the hypothalamus, central signal transduction of the "adiposity signals" leptin and insulin (both inhibit food intake) and of the food intake stimulating hormone ghrelin was investigated comprehensively. Another aim of this thesis was the identification of the molecular identity underlying the phenomenon of leptin resistance, a key event in the onset of obesity. Furthermore, possible convergence of central leptin- and insulin signalling pathways was investigated. The hypothalamic signal transduction of both hormones was strikingly seasonally regulated implying a central role of these humoral signals in mediating seasonal body weight changes. The molecular identity of seasonally induced leptin resistance could be unravelled: It is caused by modulation of the signal transduction cascade distal to the leptin receptor. Moreover, the results of this thesis contradict to the popular opinion of possible synergistic effects conveyed by the anorexigenic hormones leptin and insulin which are related to their hypothalamic signalling. Ghrelin and its central signalling by the ghrelin receptor is very likely responsible for the acute regulation of food intake whereas it does not act on chronic changes in energy homeostasis (seasonal body weight cycles)

Short photoperiod-induced decrease of histamine H3 receptors facilitates activation of hypothalamic neurons in the Siberian Hamster

Nonhibernating seasonal mammals have adapted to temporal changes in food availability through behavioral and physiological mechanisms to store food and energy during times of predictable plenty and conserve energy during predicted shortage. Little is known, however, of the hypothalamic neuronal events that lead to a change in behavior or physiology. Here we show for the first time that a shift from long summer-like to short inter-like photoperiod, which induces physiological adaptation to winter in the Siberian hamster, including a body weight decrease of up to 30%, increases neuronal activity in the dorsomedial region of the arcuate nucleus (dmpARC) assessed by electro physiological patch-clamping recording. Increased neuronal activity in short days is dependent on a photoperiod-driven down-regulation of H3 receptor expression and can be mimicked in long-day dmpARC neurons by the application of the H3 receptor antagonist, clobenproprit. Short-day activation of dmpARC neurons results in increased c-Fos expression. Tract tracing with the trans-synaptic retrograde tracer, pseudorabies virus, delivered into adipose tissue reveals a multisynaptic neuronal sympathetic outflow from dmpARC to white adipose tissue. These data strongly suggest that increased activity of dmpARC neurons, as a consequence of down-regulation of the histamine H3 receptor, contributes to the physiological adaptation of body weight regulation in seasonal photoperiod

What makes Tanzanian smallholder farmers satisfied with their life? It’s not farming!

It is widely assumed that farmers want to farm and that successful farming is positively associated with a farmer’s life satisfaction. Accordingly, especially development interventions in the Global South are focussed on upgrading and transforming rural farming landscapes under the general premise of raising productivity. However, growing evidence suggests that the assumed centrality of farming for life satisfaction is in question. The rise of trans-local and diversified livelihoods is permeating rural landscapes and new rural hopes, aspirations and livelihoods include more than “ just farming”. This study responds to a simple question: What makes smallholder farmers satisfied with their life? In doing so, it uses the case study of two agricultural clusters in Tanzania which have recently received massive financial and donor support to upgrade and transform smallholder agriculture. Based on survey data with 865 farming households, we use a multivariate logistic regression model to test for the effects of different agricultural and non-agricultural livelihood assets on the life satisfaction of smallholders. Our results suggest that just improving productivity-enhancing agricultural assets (agricultural capital, output, knowledge) is not significantly raising smallholders’ life satisfaction. Rather, more fundamental livelihood assets such as positionality (gender and age), savings and housing conditions have the strongest effect

SerpinA3N is a novel hypothalamic gene upregulated by a high-fat diet and leptin in mice

Background: Energy homeostasis is regulated by the hypothalamus but fails when animals are fed a high-fat diet (HFD), and leptin insensitivity and obesity develops. To elucidate the possible mechanisms underlying these effects, a microarray-based transcriptomics approach was used to identify novel genes regulated by HFD and leptin in the mouse hypothalamus. Results: Mouse global array data identified serpinA3N as a novel gene highly upregulated by both a HFD and leptin challenge. In situ hybridisation showed serpinA3N expression upregulation by HFD and leptin in all major hypothalamic nuclei in agreement with transcriptomic gene expression data. Immunohistochemistry and studies in the hypothalamic clonal neuronal cell line, mHypoE-N42 (N42), confirmed that alpha 1-antichymotrypsin (α1AC), the protein encoded by serpinA3, is localised to neurons and revealed that it is secreted into the media. SerpinA3N expression in N42 neurons is upregulated by palmitic acid and by leptin, together with IL-6 and TNFα, and all three genes are downregulated by the anti-inflammatory monounsaturated fat, oleic acid. Additionally, palmitate upregulation of serpinA3 in N42 neurons is blocked by the NFκB inhibitor, BAY11, and the upregulation of serpinA3N expression in the hypothalamus by HFD is blunted in IL-1 receptor 1 knockout (IL-1R1−/−) mice. Conclusions: These data demonstrate that serpinA3 expression is implicated in nutritionally mediated hypothalamic inflammation

Glycaemic Response to a Nut-Enriched Diet in Asian Chinese Adults with Normal or High Glycaemia: The Tū Ora RCT

Nut-based products are a good source of high-quality plant protein in addition to mono- and polyunsaturated fatty acids, and may aid low-glycaemic dietary strategies important for the prevention of type 2 diabetes (T2D). In particular, they may be advantageous in populations susceptible to dysglycaemia, such as Asian Chinese. The present study aimed to compare effects of a higher-protein nut bar (HP-NB, also higher in total fibre and unsaturated fats, comprising mixed almonds and peanuts) vs. an isoenergetic higher-carbohydrate cereal bar (HC-CB) within the diet of 101 Chinese adults with overweight and normo- or hyperglycaemia. Ectopic pancreas and liver fat were characterised using magnetic resonance imaging and spectroscopy (MRI/S) as a secondary outcome. Participants were randomized to receive HP-NB or HC-CB daily as a 1 MJ light meal or snack replacement, in addition to healthy eating advice. Anthropometry and clinical indicators of T2D risk were assessed fasted and during an oral glucose tolerance test (OGTT), pre- and post-intervention. No significant difference was observed between diet groups for body weight, body mass index, waist or hip circumference, blood pressure, glucoregulatory markers, lipid profile or inflammatory markers over 12 weeks (all, p > 0.05). No difference was observed between glycaemic subgroups or those with normal versus high ectopic organ fat. Although HP-NB can attenuate postprandial glycaemia following a meal, no effects were observed for either fasting or glucose-mediated outcomes following longer-term inclusion in the habitual diet of Chinese adults with overweight, including at-risk subgroups.fals

Glycaemic Response to a Nut-Enriched Diet in Asian Chinese Adults with Normal or High Glycaemia: The Tū Ora RCT

\ua9 2024 by the authors. Nut-based products are a good source of high-quality plant protein in addition to mono- and polyunsaturated fatty acids, and may aid low-glycaemic dietary strategies important for the prevention of type 2 diabetes (T2D). In particular, they may be advantageous in populations susceptible to dysglycaemia, such as Asian Chinese. The present study aimed to compare effects of a higher-protein nut bar (HP-NB, also higher in total fibre and unsaturated fats, comprising mixed almonds and peanuts) vs. an isoenergetic higher-carbohydrate cereal bar (HC-CB) within the diet of 101 Chinese adults with overweight and normo- or hyperglycaemia. Ectopic pancreas and liver fat were characterised using magnetic resonance imaging and spectroscopy (MRI/S) as a secondary outcome. Participants were randomized to receive HP-NB or HC-CB daily as a 1 MJ light meal or snack replacement, in addition to healthy eating advice. Anthropometry and clinical indicators of T2D risk were assessed fasted and during an oral glucose tolerance test (OGTT), pre- and post-intervention. No significant difference was observed between diet groups for body weight, body mass index, waist or hip circumference, blood pressure, glucoregulatory markers, lipid profile or inflammatory markers over 12 weeks (all, p > 0.05). No difference was observed between glycaemic subgroups or those with normal versus high ectopic organ fat. Although HP-NB can attenuate postprandial glycaemia following a meal, no effects were observed for either fasting or glucose-mediated outcomes following longer-term inclusion in the habitual diet of Chinese adults with overweight, including at-risk subgroups